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Stress. Author manuscript; available in PMC 2020 September 01.
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Published in final edited form as:

Stress. 2019 September ; 22(5): 530–547. doi:10.1080/10253890.2019.1621283.
Common pathways and communication between the Brain and

Heart: Connecting post-traumatic stress disorder and heart
failure
Marlene A. Wilson*,1, Israel Liberzon2, Merry L. Lindsey3, Yana Lokshina2, Victoria B.
Risbrough4, Renu Sah5, Susan K. Wood1, John B. Williamson6, Francis G. Spinale7
1Department of Pharmacology, Physiology and Neuroscience, University of South Carolina
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School of Medicine and Research Service, Columbia VA Health Care System, Columbia SC
2Department of Psychiatry, Texas A&M College of Medicine, Bryan, TX
3Departmentof Cellular and Integrative Physiology, University of Nebraska Medical Center, and
Research Service, Omaha VA Medical Center, Omaha NE
4VA Center of Excellence for Stress and Mental Health, La Jolla CA, Dept. of Psychiatry,
University of California San Diego
5Department of Pharmacology and Systems Physiology, University of Cincinnati College of
Medicine, Cincinnati, OH
6Department of Neurology, University of Florida College of Medicine, Gainesville FL
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7Departmentof Cell Biology and Anatomy, University of South Carolina School of Medicine and
Research Service, Columbia VA Health Care System., Columbia SC
Abstract
Psychiatric illnesses and cardiovascular disease (CVD) contribute to significant overall morbidity,
mortality and health care costs, and are predicted to reach epidemic proportions with the aging
population. Within the Veterans Administration (VA) health care system, psychiatric illnesses such
as post-traumatic stress disorder (PTSD) and CVD such as heart failure (HF), are leading causes of
hospital admissions, prolonged hospital stays, and resource utilization. Numerous studies have
demonstrated associations between PTSD symptoms and CVD endpoints, particularly in the
Veteran population. Not only does PTSD increase the risk of HF, but this relationship is bi-
directional. Accordingly, a VA-sponsored conference entitled “Cardiovascular Comorbidities in
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PTSD: The Brain-Heart Consortium” was convened to explore potential relationships and
common biological pathways between PTSD and HF. The conference was framed around the
hypothesis that specific common systems are dysregulated in both PTSD and HF, resulting in a
synergistic acceleration and amplification of both disease processes. The conference was not
intended to identify all independent pathways that give rise to PTSD and HF, but rather identify
*
Corresponding author information: Marlene A. Wilson, Department of Pharmacology, Physiology and Neuroscience, University of
South Carolina School of Medicine, Columbia SC 29208, Research Service, Columbia VA Health Care System, Columbia SC 29209,
Marlene.Wilson@uscmed.sc.edu; 803-216-3507.
Other Authors (MAW, MLL, YL, VBR, RS, SKW, JBW, FGS) have no disclosures to report.
Wilson et al. Page 2
shared systems, pathways, and biological mediators that would be modifiable in both disease
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processes. The results from this conference identified specific endocrine, autonomic, immune,
structural, genetic, and physiological changes that may contribute to shared PTSD-CVD
pathophysiology and could represent unique opportunities to develop therapies for both PTSD and
HF. Some recommendations from the group for future research opportunities are provided.
Keywords
post-traumatic stress disorder; cardiovascular disease; heart failure; inflammation; orexin/
hypocretin; Veterans Affairs
Introduction
Psychiatric illnesses and cardiovascular disease (CVD) contribute to significant overall
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morbidity, mortality and health care costs, particularly within the Veterans Administration
(VA) health care system. Specifically, by virtue of the demographics and background of the
VA patient population, the co-existence of post-traumatic stress disorders (PTSD) and heart
failure (HF) is prevalent (Buckley & Kaloupek, 2001; B. E. Cohen, Marmar, Ren,
Bertenthal, & Seal, 2009; Kubzansky, Koenen, Spiro, Vokonas, & Sparrow, 2007; Pole,
2007). Numerous studies have demonstrated associations between PTSD symptoms and
cardiovascular endpoints. The presence of either self-reported or physician-rated PTSD is
associated with increases in readmissions for cardiovascular events such as myocardial
infarction (MI), angina, hypertensive complications, atrioventricular conduction deficits, and
arterial disease, which can culminate in the development and progression of HF and
cardiovascular-related mortality (Gander & von Kanel, 2006). Further studies continue to
describe associations between PTSD and CVD, particularly in the Veteran population (B. E.
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Cohen et al., 2009; Crum-Cianflone et al., 2014; Jordan et al., 2013; Kibler, Tursich, Ma,
Malcolm, & Greenbarg, 2014). In a meta-analysis of six studies, even after adjusting for
comorbid depression, PTSD was an independent risk factor for incident coronary heart
disease and cardiac-specific mortality (Edmondson, Kronish, Shaffer, Falzon, & Burg,
2013). Vietnam Veterans with PTSD were more likely to have evidence of atrioventricular
conduction defects and a greater history of myocardial infarction (MI) (Boscarino & Chang,
1999), while in a community-based sample, Veterans with PTSD had increased risk for
developing HF compared with Veterans without PTSD (Roy, Foraker, Girton, & Mansfield,
2015), and PTSD is associated with a greater mortality in patients with HF (Fudim et al.,
2018). Within the Veteran population, MI is one of the top five causes of cardiovascular
hospital admission (Krishnamurthi, Francis, Fihn, Meyer, & Whooley, 2018) and Veterans
are at higher risk of having new onset of CVD compared with non-Veterans (Assari, 2014).
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Even after controlling for all covariates, logistic regression confirmed the association
between Veteran status and heart disease (adjusted relative risk = 1.483, 95% confidence
interval = 1.176–1.871) (Assari, 2014). Thus in general, PTSD is associated with more than
double the risk for ischemia and CVD events (Turner, Neylan, Schiller, Li, & Cohen, 2013).
In addition to PTSD-associated risks in developing CVD, the manifestation of CVD can in

and of itself serve as a traumatic event, and studies suggest that the prevalence of PTSD is

about 10–20% following acute coronary syndromes (Edmondson et al., 2012; Gander & von
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Kanel, 2006). More critically, PTSD symptoms after these cardiovascular events increased
the risk of adverse cardiovascular outcomes (Edmondson & Cohen, 2013), predicted non-
adherence to medication, and increased likelihood of CVD readmission over the first year
(Shemesh et al., 2004). A recent study demonstrated lower coronary distensibility index
(CDI) scores, which are associated with endothelial dependent plaque composition, in
patients with PTSD, and PTSD was independently associated with an increased risk of
major adverse cardiovascular events (MI or CVD death) over a 50 month follow-up (Ahmadi
et al., 2018). Several past reviews have suggested a variety of factors might contribute to this
comorbidity between PTSD and CVD, and particularly HF, including biologic factors such
as dysregulation of the autonomic nervous system (ANS), hypothalamic-pituitary-adrenal
axis (HPA), oxidative stress, and inflammation (B.E. Cohen, Edmondson, & Kronish, 2015;
Edmondson & Cohen, 2013; Gander & von Kanel, 2006). These complex
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neurophysiologically regulated systems may reflect and/or influence changes in

psychological factors that interact with drug use, eating behaviors, maladaptive aging, and
physiological processes such as metabolic disease (Wolf & Morrison, 2017).
Based on the existing comorbidity of PTSD and HF within the VA health system and in light
of the associations briefly described in the preceding section, a VA sponsored conference
entitled “Cardiovascular Comorbidities in PTSD: The Brain-Heart Consortium” was
convened in July 2017 (Columbia, SC; attendee list presented in Table 1) to explore
potential relationships and common biological pathways between PTSD and HF. The theme
of the conference was framed around the hypothesis that specific common systems are
dysregulated in both PTSD and HF, resulting in a synergistic acceleration and amplification
of both disease processes. This conference was not intended to identify all independent
pathways that give rise to PTSD and HF, but rather identify shared systems, pathways, and
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biological mediators that would be modifiable in both disease processes. The purpose of this
report is to summarize key points from this conference and frame common themes which
emerged regarding the comorbidity between PTSD and HF, as well as the recommendations
from the group for future research opportunities.
Section 1. Symptoms and Etiology

PTSD Symptoms and Etiology
PTSD is a debilitating psychiatric disorder that develops in a subset of individuals after
exposure to traumatic events and is associated with pervasive functional impairment and
increased health problems, including CVD and sleep dysregulation (see sections above and
below). From the clinical perspective, PTSD is defined as a Trauma- and Stressor-Related
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Disorders with four distinct clusters of symptoms in the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5; American Psychiatric Association, 2013) Thus, PTSD requires
exposure to a traumatic or stressful event as a diagnostic criterion (Criterion A), which is
clarified as directly experiencing a traumatic event or witnessing the event in person,
experiencing repeated or extreme exposure to aversive details in the aftermath of a traumatic
event, or learning about the violent or unexpected death of a close facility member or friend.
In DSM-5, the four symptom clusters defined for PTSD include re-experiencing, avoidance,

negative cognitions and mood, and arousal/reactivity. Re-experiencing refers to having

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spontaneous memories, recurrent dreams, or flashbacks of the traumatic event, or

psychological or physical distress associated with cues related to the event, while avoidance
refers to avoiding the distressing memories, thoughts, feelings, or external reminders of the
event. The cluster of negative alterations in cognitions and mood incorporates a broad
spectrum of symptoms, including those that were originally referred to as “emotional
numbing” associated with feelings of estrangement from others, diminished interest in
activities, inability to experience positive emotions, or inability to recall key aspects of the
event, in addition to having a generally negative emotional state with exaggerated negative
expectations and distorted blame concerning both self and others. Finally, arousal can be
associated with aggressive, angry, reckless, or self-destructive behavior, sleep disturbances,
exaggerated startle, or hyper-vigilance, incorporating both the “flight” and the “fight”
aspects of the stress response associated with PTSD (Wilson & Reagan, 2016).
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While estimates suggest that somewhere between 50 and 84% of the general population will
experience a traumatic event, most individuals are resilient to these stressors, with ~10% of
the population subsequently developing PTSD. Estimates of the lifetime or past twelve-
month prevalence of PTSD using the DSM-IV or DSM-5 criteria among adult Americans
were 6.1–6.8% and 3.5–4.7 %, respectively, and these values were higher for women than
men (Goldstein et al., 2016; Kessler, Berglund, et al., 2005; Kessler, Chiu, Demler,
Merikangas, & Walters, 2005). Importantly, rates among combat veterans are much higher,
with estimates for the prevalence of PTSD among the total Gulf War Veteran population to
be 10.1% (Kang, Natelson, Mahan, Lee, & Murphy, 2003) and for deployed Operation
Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) (Afghanistan and Iraq) service
members to be 13.8% (Tamelian & Jaycox, 2008).
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Brain systems involved in PTSD

PTSD can be reflected by altered activity in multiple brain systems, including those that
directly modify autonomic functions. Functional neuroimaging studies over the past two
decades have implicated PTSD-specific changes in regional activation and functional
connectivity. More specifically, hyper-activation of amygdala, insula, dorsal anterior
cingulate cortex (dACC), as well as hypo-activation in ventral medial prefrontal cortex
(vmPFC) and impaired hippocampal function have been consistently detected (Lebois,
Wolff, & Ressler, 2016; Liberzon & Abelson, 2016; Pitman et al., 2012; Stark et al., 2015).
Furthermore, PTSD has been associated with altered connectivity within different neural
circuits (Liberzon & Abelson, 2016). These changes in brain function are consistent with the
autonomic features of neurophysiological defense mechanisms associated with increased
detection of threat in the environment. PTSD has been associated with attentional bias
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towards threat and, consequently, exaggerated threat detection, manifested in increased

connectivity within salience network and heightened responsivity of insula, amygdala and
dACC (Liberzon & Abelson, 2016). Autonomic neurophysiological states can be influenced
by disruption in the hierarchically organized brain systems that comprise the central
autonomic network (Williamson, Porges, Lamb, & Porges, 2014). Ventrolimbic (orbito-
prefrontal cortex, anterior temporal lobe, amygdala) and thalamo-cortical pathways are
important in the regulation of emotion and the intersection of emotion and autonomic

responses. The dynamic activity between these autonomic brain systems is chronically
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modified by PTSD and diminishes the ability to shift to a safe neurophysiological state.
Indeed, PTSD has been found to be associated with altered fear extinction (i.e., deficits in
learning that cues once associated with trauma are now safe) and fear overgeneralization (i.e.
diminished capacity to discriminate between dangerous and safe cues) (Jovanovic, Kazama,
Bachevalier, & Davis, 2012). When an individual feels safe, bodily state is efficiently
regulated; this is accomplished through the influence of myelinated vagal efferent pathways.
Beyond these behavioral implications of vagus nerve activation, vagal efferent pathways
oppose fight or flight mechanisms (i.e., sympathetic nervous system). Therefore prefrontal-
limbic brain circuits regulating behavior and terminating on vagal centers (dorsal motor
nucleus of the vagus (DMV) or nucleus ambiguus) are poised to promote PTSD-like
behaviors and cardiovascular dysfunction. For example, enhanced amygdalar activity is
associated with increased sympathetic nervous system response to stress, as well as fear-
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conditioned cardiovascular responses (Powell et al., 1997), while PFC activity serves to
suppress sympathetic nervous system activity (Verberne & Owens, 1998). Moreover,
hyperactivity of the locus coeruleus (LC), a brain region that regulates both arousal and
cardiac autonomic function has also been detected in PTSD (Krystal et al., 2018; Naegeli et
al., 2018). Importantly, norepinephrine (NE) is released from the neurons of the LC
projecting to various brain regions implicated in the stress response, including DMV,
hippocampus, PFC, amygdala, hypothalamus, and thalamus (Hendrickson & Raskind,
2016). The coeruleo-vagal pathway (ie., LC-DMV) provides a circuit by which the LC-NE
system can inhibit activity of DMV neurons by binding to α2-adrenoceptors (Samuels &
Szabadi, 2008). As such, activation of the LC not only produces arousal, but decreases
vagal/increases sympathetic tone. There is mounting evidence for LC noradrenergic
regulation of the circuit connecting the hippocampus with vmPFC; hypo-activation of the
hippocampus and vmPFC, as well as reduced connectivity within this circuit, is likely to
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contribute to context processing deficits that could provoke dominance of fear over safety
memories, inappropriate responsivity to trauma-associated cues, and hypervigilance in
PTSD (Jin & Maren, 2015; Liberzon & Abelson, 2016). Additionally, PTSD-related
biological abnormalities are likely to include a neural circuit that connects the hypothalamus
and amygdala with the LC, in which corticotropin releasing factor (CRF) and NE interact to
increase fear conditioning and encoding of emotional memories, enhance arousal and
vigilance, and integrate endocrine responses to stress (Hendrickson & Raskind, 2016).
Animal Models of PTSD

A comprehensive understanding of PTSD biomarkers, including neurocircuits, autonomic
dysregulation, neurotransmitter abnormalities, and increased inflammation, requires
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mechanistic studies using animal models, as much of the experimental work is not feasible
in humans (Pitman et al., 2012). There is a large array of potential animal models of PTSD
(see Table 2), however most concentrate on inducing a severe trauma (i.e. shock, predator
exposure, prolonged restraint, or multiple stressors within a 24–48 hr period), allowing the
animals to rest for at least 7 days and then assessing enduring behavioral and physiological
phenotypes (Deslauriers, Powell, & Risbrough, 2017; Deslauriers, Toth, Der-Avakian, &
Risbrough, 2018). Models that adhere to relatively short severe trauma exposures are
predator exposure (Deslauriers, Toth, et al., 2018; Zoladz & Diamond, 2016), single

prolonged stress (SPS)(Lisieski, Eagle, Conti, Liberzon, & Perrine, 2018) and fear
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conditioning augmented by additional stressors (Perusini et al., 2015). Models that utilize
chronic trauma exposure, often resulting in greater enduring depressive-like behavior are
social defeat stress and chronic unpredictable stress (Deslauriers, Toth, et al., 2018; Finnell
et al., 2017; Finnell et al., 2018). Both the single severe trauma and the chronic trauma
exposure models induce enduring anxiety-like responses, however the chronic stress models
tend to recapitulate aspects of depression that are not associated with PTSD, such as blunted
HPA axis while single severe stressors are associated with higher arousal and HPA
hypersensitivity observed in PTSD (Deslauriers, Toth, et al., 2018).
The animal models shown in Table 2 have proven to be a useful tool for examining the
molecular and cellular physiological mechanisms implicated in PTSD pathology that may be
the targets for interventions (Deslauriers et al., 2017). For example these models have been
critical in showing that neurotransmitter abnormalities and other molecular mechanisms
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induced by trauma occur within a specific anatomical context (i.e., within specific
neurocircuits or cell types), which will be critical for development of potential interventions.
Some models are also clearly associated with immune mechanisms that may also converge
with CVD mechanisms (e.g. social defeat stress, predator stress and single prolonged stress
(see Table 2)) (Deslauriers et al., 2017; Deslauriers, Toth, et al., 2018). Traumatic stress in
animals has been shown to induce similar enduring effects on cardiovascular functions as
those observed in PTSD patients, including reductions in heart rate variability (HRV),
increased blood pressure, and heart damage (Table 2) (Bruijnzeel, Stam, Croiset, & Wiegant,
2001; Carnevali et al., 2013; Crestani, 2016; Koresh et al., 2016; Laukova et al., 2014;
Lazuko et al., 2018; Liu et al., 2016; Penna & Bassani, 2010; Rorabaugh et al., 2015; Vieira
et al., 2018; Zoladz & Diamond, 2016). Importantly however, effects on cardiovascular
function can be highly dependent on type and duration of stressor (predictable vs.
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unpredictable, and chronicity) (Crestani, 2016) and sex or gonadal hormones (Finnell et al.,
2017; Finnell et al., 2018; Vieira et al., 2018), suggesting that careful consideration of the
cardiovascular phenotypes under investigation must guide model selection.
HF Definition and Relation to PTSD

Similar to PTSD, HF is defined by a presentation of a constellation of symptoms rather than
the underlying causality or etiology (Tanai & Frantz, 2015). HF consumes over 25% of total
US health expenditures and is predicted to reach unsustainable levels by 2050 (Writing
Group et al., 2016). The spectrum of HF symptomatology is usually one of increased fluid
accumulation, reduced exercise tolerance, and as the disease progresses, activation of a
number of neurohormonal systems and inflammatory cascades. One important development
in the clinical management of HF was to recognize that HF is a generalized term and not a
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specific diagnosis. Thus, two distinct HF phenotypes have emerged which are defined not by
symptom presentation, but rather by underlying pathophysiology. Specifically, patients
presenting with HF and reduced left ventricular (LV) forward stroke volume, or ejection
fraction, are defined as HF with reduced ejection fraction (HFrEF) whereas patients
presenting with HF, a relatively normal LV ejection fraction but impaired LV filling are
defined as HF with preserved ejection fraction (HFpEF). The predominant cause for HFrEF
is ischemic heart disease such as following MI, whereas the predominant cause for HFpEF is

prolonged LV afterload such as with hypertension; however these CVD conditions are not
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mutually exclusive and are also influenced by age, body mass index, and other
environmental factors (Ezekowitz et al., 2009). In a recent study, nearly 10% of the Veterans
diagnosed with HFrEF had PTSD, and these patients had a higher burden of comorbidities
(Fudim et al., 2018). These specific HF phenotypes are also important in terms of guiding
therapy whereby device driven therapies such as cardiac resynchronization therapy and LV
assist devices have demonstrated efficacy in HFrEF, but not in HFpEF. On the other hand,
pharmacotherapies such as inhibition of sympathetic or renin-angiotensin pathways can be
effective in both forms of HF. Thus, not dissimilar to PTSD, identifying the specific form
and feature of HF as well as the activation of underlying pathways hold relevance as to
therapeutic strategies.
While HF is due to impairments in LV functional performance, this results in systemic

manifestations which affect all organ systems and the brain is not protected. Cerebral
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symptoms of HF include confusion, sleep disorders, dizziness, altered mood, and

disorientation. There is also a link between impaired cognitive function and cardiac
dysfunction that has been termed cardiogenic dementia. There are a number of shared risk
factors between heart and brain, including perfusion abnormalities and rheological
alterations. Manifestations of impaired cerebral physiology include fluctuating delirium
precipitated by acute cardiac decompensation and chronic impaired cerebral function during
periods of stable HF.
A major common feature between brain and heart is the limited capacity for the major cell
types (neurons and cardiomyocytes) to repair and regenerate. In response to injury,
cardiomyocyte responses include hypertrophy or cell death through a number of means
including apoptosis and necrosis. Increased intracellular calcium concentrations and cyclic
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AMP formation is a common feature of cardiomyocyte responses to stress. While increased

intracellular calcium has positive inotrope and negative lusitrope effects to increase
contractility and reduce relaxation times, excess calcium entry can be a conduit for
arrhythmias. In response to injury that induces neuron or cardiomyocyte loss, both brain and
heart respond by stimulating an inflammatory response that initiates a wound healing
cascade. The extracellular matrix (ECM) is a critical component, serving to both amplify
and regulate inflammation as well as providing ECM proteins that serve as scar tissue
(Lindsey, 2018; Spinale et al., 2016).
Animal Models of Heart Failure

As with models of PTSD, there are no animal models of HF which completely recapitulate
this complex disease process. However, the first consideration is the HF phenotype to be
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studied for inducing the initiating stimulus in the appropriate animal model. For HFrEF, the
most common approach is to induce MI through coronary ligation in both small and large
animals. For HFpEF, inducing LV pressure overload either mechanically (aortic constriction)
or pharmacologically (infusion of vasopressor agents) are commonly employed. There are a
number of reviews which identify the strengths and inherent weaknesses of these animal
models. Depending upon the stimulus, there is every possibility of superimposing a PTSD
stimulus and HF induction in the same animal, and is identified further in the future

directions section. In terms of relevance to superimposing a form of PTSD and HF, rodent
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models would most likely be the exploratory start point (Horgan, Watson, Glezeva, &
Baugh, 2014; Houser et al., 2012; Lindsey et al., 2018).
Section 2: Autonomic nervous system (ANS) in PTSD and HF

PTSD is an autonomic disorder: Hyperarousal features
It has been established that PTSD is associated with ANS dysregulation such as diminished
activity of the parasympathetic nervous system (PNS) linked to vegetative and restorative
functioning, and elevated activity of the sympathetic nervous system (SNS) related to
mobilization of energy and stimulation of the fight or flight response (Blechert, Michael,
Grossman, Lajtman, & Wilhelm, 2007; Brudey et al., 2015; Clausen, Aupperle, Sisante,
Wilson, & Billinger, 2016; Green et al., 2016). Disorder-related alterations in PNS and SNS
function in the setting of PTSD pathophysiology are reflected by an elevated heart rate
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and/or systemic arterial pressure, increased galvanic skin response (a pure measure of SNS
activity) to startle, and increased ANS responses to trauma-related cues (Keary, Hughes, &
Palmieri, 2009; McFall, Murburg, Ko, & Veith, 1990; Paulus, Argo, & Egge, 2013; Pole,
2007). Further, PNS disturbances have been reported including attenuated resting high
frequency heart rate variability (HRV) or vagal tone as defined by respiratory sinus
arrhythmia (RSA) (Sack, Hopper, & Lamprecht, 2004), since RSA represents a non-invasive
index of parasympathetic control of heart rate. These associations are detectable even when
controlling for depression and traumatic brain injury, two highly comorbid conditions in
PTSD that are also associated with low HRV (Minassian et al., 2014). Twin studies have
suggested that the reduced HRV associated with PTSD is not related to heritable factors, but
may be related to symptom state (Shah et al., 2013), with resolution of RSA differences after
successful treatment of PTSD. Prospective longitudinal studies, however, suggest that
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reduced HRV may be a risk factor for development of PTSD (Minassian et al., 2015), hence
convergent risk factors in autonomic control could contribute to PTSD and CVD
comorbidity. Consistent with SNS hyperactivity, exaggerated catecholamine responses to
trauma-related stimuli have been reported in PTSD, as well as higher baseline levels of
norepinephrine and epinephrine in CSF, plasma, and urine in patients with PTSD (Liberzon,
Abelson, Flagel, Raz, & Young, 1999; Pitman et al., 2012; Southwick et al., 1999; Strawn &
Geracioti, 2008; Yehuda et al., 1998). These autonomic features of PTSD are associated with
the development of CVD even in subclinical populations. Thus, several features in the
resting heart rate spectra are correlated with mortality (Williamson et al., 2010), low
frequency HRV is an independent predictor of death (Tsuji et al., 1994), and reduced low
frequency HRV is linked to coronary artery disease and increased stroke risk (Binici,
Mouridsen, Kober, & Sajadieh, 2011; Kotecha et al., 2012). Furthermore, disruption in
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neurophysiological regulation of emotion seen in PTSD may manifest as anger or depression

or anxiety, and these changes in emotional state modify psychosocial behaviors including
the ability to adaptively socially engage, resulting in loneliness. All of these emotional states
are associated with modifications in ANS and the developmental of systemic diseases
including CVD. Patients with PTSD have higher rates of aggression and anger (Novaco &
Chemtob, 2002) and PTSD severity is a significant predictor of intermittent explosive
disorder diagnosis (Reardon et al., 2014). Hostility is related to exaggerated autonomic

reactivity to cognitive or pain stressors, reduced heart rate variability, and cardiovascular
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disease (Sloan et al., 2001; Williamson & Harrison, 2003). These co-morbid symptoms/traits
rely on the same brain systems, supporting the idea that shifts in autonomic states impact
aspects of mood/personality in a predictable manner.
Autonomic dysfunction in HF
The sympathetic system is similarly activated during the progression to HF, resulting in
activation of pressure baroreceptors in the carotid sinus, aortic arch, and LV (Grassi,
Seravalle, & Mancia, 2015). Afferent signals stimulate the central cardiovascular center in
the brain to increase circulating blood volume. As a result of sympathetic activation,
arginine vasopressin is released from the posterior pituitary gland and perfusion is
redistributed systemically, including in the heart, kidney, vasculature, and skeletal muscles.
Persistent sympathetic activation causes transcriptional and posttranscriptional changes at
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the level of the genome. Activation of the sympathetic system is a rapid response mechanism
for adaptation to HF. Baroreceptors are stimulated in response to stretch activation, and the
precise balance between low and high pressure systems shifts, such that baroreceptor
inhibition falls and excitatory impulses rise. Like PTSD, the general increase in SNS activity
is accompanied by a decrease in PNS activation, leading to reduced HRV, elevated blood
pressure, and elevated peripheral resistance (Grassi et al., 2015; Parati & Esler, 2012). This
in turn activates the renin-angiotensin-aldosterone system to regulate the salt-fluid balance.
Plasma norepinephrine increases and correlates with mortality in patients with advanced HF
(Slavikova, Kuncova, & Topolcan, 2007). Both β1 and α1-adrenergic receptors are often
stimulated in HF, and the use of β adrenergic antagonists constitutes a standard of care
(Najafi, Sequeira, Kuster, & van der Velden, 2016). Thus, in the context of PTSD and HF
prolonged sympathetic activation can be particularly detrimental and exacerbate both disease
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processes.
Hyperarousal Features of Sleep and Autonomic Imbalance in PTSD and HF

Sleep disruption is amongst the most prevalent symptoms of PTSD and HF, with co-
occurring sleep disorders diagnosable in approximately 50–70% of patients (Pak et al.,
2018; Spoormaker & Montgomery, 2008). Sleep dysregulation is related to ANS activity,
and the hyperarousal features of PTSD are particularly associated with sleep problems (van
Wyk, Thomas, Solms, & Lipinska, 2016). In order to shift from a defensive disposition to
one conducive to good sleep, the individual needs to determine safety and inhibit the more
primitive limbic structures that control fight, flight, or freeze behaviors (Porges, Doussard-
Roosevelt, Stifter, McClenny, & Riniolo, 1999). Although sleep is regulated through
complicated interactions between multiple brain regions and neuromodulators, the vagally-
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mediated components of the limbic system are critical to normal sleep function (Porges et
al., 1999). Parasympathetic activity normally increases as people transition to sleep and is
critical to sleep efficiency (Jung, Lee, Jeong, & Park, 2017; Woodward et al., 2009).
Common complaints in patients with PTSD include nightmares, distressed awakenings,

sleep terrors, insomnia, and nocturnal panic attacks (Spoormaker & Montgomery, 2008). A
meta-analysis of sleep quality in PTSD showed decreased slow wave sleep, and longer sleep
latencies (Kobayashi, Boarts, & Delahanty, 2007). During slow wave sleep, there is a decline

in mean arterial pressure in comparison to wakefulness, and a lack of reduction in mean

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arterial pressure is associated with CVD risk (Silvani, Bastianini, Berteotti, Lo Martire, &
Zoccoli, 2013). The relationship of PTSD to sleep disruption is bidirectional, since PTSD
increases the likelihood of sleep problems and PTSD is exacerbated by sleep problems.
Further, sleep quality is a vulnerability factor for the development of PTSD, suggesting that
sleep quality and PTSD are mechanistically linked (El-Solh, Riaz, & Roberts, 2018; van
Liempt, 2012). This may involve dysregulation of the ANS, since nocturnal autonomic
changes including lack of reduction in blood pressure are associated with hyperarousal
symptoms of PTSD, greater sleep-related daytime dysfunction, poorer overall sleep quality,
and more frequent use of sleep medication. This dysregulation of parasympathetic control
during sleep may contribute to enhanced risk for CVD (Ulmer, Calhoun, Bosworth, Dennis,
& Beckham, 2013; Ulmer, Hall, Dennis, Beckham, & Germain, 2018). People with PTSD
show lower respiratory sinus arrhythmia (RSA) during sleep (Woodward et al., 2009) which
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is linked to increased stroke risk (Binici et al., 2011), and treating sleep quality may improve
symptoms of PTSD (Ho, Chan, & Tang, 2016).
A clear relationship has also been established with respect to CVD and sleep disturbances.
Similar to PTSD, patients with HF often have disrupted sleep, and while there is an
association between untreated obstructive sleep apnea and mortality in patients with HF,
patients with heart failure often do not report excessive daytime sleepiness (Pak et al., 2018).
Notably, sleep apnea both due to obstructive causes as well as centrally mediated (central
sleep apnea; CSA), can contribute to the progression of CVD such as heart failure (Drager et
al., 2017). For example, up to 40% of patients presenting with HF also have been identified
to have sleep apnea (H. Wang et al., 2007). This specific sleep disorder likely contributes to
the progression of the HF process due to the episodic hypoxia/hypercapnia leading to
periods of sympathetic nervous stimulation, generation of reactive oxygen species and
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inflammation. Thus, clinical trials have been performed whereby airway management such
as continuous positive airway pressure (CPAP) was instituted to modify cardiovascular
disease progression (Drager et al., 2017). Unfortunately, in the Sleep Apnea Cardiovascular
Endpoints (SAVE) trial, in which over 2,700 patients were randomized to standard of care
with and without CPAP, there was no relative reduction in major cardiovascular events
(Bradley et al., 2005). These findings suggested that more centrally mediated approaches for
regulating CSA in the context of patients with CVD, particularly that of HF, may be more
effective. Indeed, recent clinical trials using neurostimulation approaches, particularly of the
phrenic nerve, have shown potential benefit in patients with CSA and HF (Costanzo et al.,
2016). Since this form of neurostimulation may affect both afferent and efferent pathways,
and thus modify sympathetic system outflow, then a synergistic effect may occur in patients
with both CSA and heart failure. This observed interrelationship of sleep disturbances such
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as CSA to that of cardiovascular disease, have promulgated the concept that sleep disorders
are a top tier modifiable risk factor for cardiovascular events (Drager et al., 2017). Recent
studies are also suggesting cognitive behavioral therapy might be beneficial to the sleep
disturbances in patients with HF failure, although the impact of this emerging therapeutic
approach on cardiovascular function in HF remains to be determined (Redeker et al., 2018).
Importantly, poor sleep quality is also associated with CVD factors independent of sleep
apnea (Tosur et al., 2014). Since sleep disorders are a prevalent in patients with PTSD and

HF, then the inter-relationship between pathways regulating sleep and wakefulness to that of
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CVD progression, and the role of dysregulation of the ANS in sleep disturbances, constitute
important areas for future research.
Section 3. Parallel Cell Signaling Pathways in PTSD and HF

Although discrete in many ways, the brain and heart represent parallel systems in survival,
response, and modulation. Physiologically, brain function and cardiac function are delicately
balanced by sensitive ionic gradients and fluxes orchestrated in a coordinated fashion by
numerous proteins, channels and receptors. As a consequence, it is not surprising that these
seemingly disparate tissues are both highly vulnerable to similar insults that challenge
homeostasis, such as lack of oxygen, acid-base disturbances, oxidative stress, and
inflammation. For example, reduced oxygen to both the brain and the heart yield irreversible
damage to cell types that do not regenerate (neurons and cardiomyocytes), but can induce
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similar wound-healing and repair responses. Neurons and cardiomyocytes are also
electrically excitable and communicate with other cells, making the heart and brain capable
of coordinated rhythmic or oscillatory patterns that are fundamental for their function. Thus,
an increased understanding of one system may provide valuable insight into the other
system, as well as comorbidities between cardiovascular and brain disorders.
Based on the ability of heart and brain cells to communicate with one another, and for heart
and brain to regulate function of the other, the integration of the complex microdomains and
signaling pathways is critical to normal function of both organ systems. Several common
systems impact both brain and heart, and have been suggested as possible underlying
mediators that might induce comorbidity between heart failure and PTSD (see Table 3, Table
4, and Figure 1). While beyond the scope of this review to document all potentially common
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changes, a few systems seem to be potential common mediators between PTSD and
cardiovascular disease in general and HF in particular. These changes are seen as not only
differences in signaling cascades and mediator levels in PTSD or HF patients (Table 3), but
also in genetic polymorphisms associated with these conditions (Table 4). Given the ANS
dysregulation, it is not surprising the changes in catecholamines (especially norepinephrine
and epinephrine) and their transporters, as well as α and β adrenergic receptors are seen in
both conditions, as well as changes in the cholinergic system associated with reduced
parasympathetic tone (see Tables 3 and 4)(Brudey et al., 2015; Deslauriers, Acheson, et al.,
2018 Mir, 2018 #13393; Laukkanen, Makikallio, Kauhanen, & Kurl, 2009; Liberzon et al.,
2014; Marques et al., 2017; Mir et al., 2018; Pietrzak et al., 2015; Snapir et al., 2003). As
stress-related disorders, changes are also seen in hypothalamic-pituitary-adrenal axis (HPA)
function or cortisol levels and regulators of glucocorticoid receptor signaling such as FKBP5
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(Gill, Vythilingam, & Page, 2008; Lebois et al., 2016; Lovallo et al., 2016; Miller,
McKinney, Kanter, Korte, & Lovallo, 2011), as well as several aspects of the renin-
angiotensin system and polymorphisms in angiotensin converting enzyme, angiotensin
levels, and angiotensin receptors (Cameron et al., 2006; Nylocks et al., 2015; Raynolds et
al., 1993; Winkelmann et al., 1999; Wu et al., 2009). An emerging literature suggests the
endocannabinoid system may be a common mediator for cardiovascular and PTSD related
changes (Hill, Campolongo, Yehuda, & Patel, 2018; Pacher, Steffens, Hasko, Schindler, &
Kunos, 2018). In HF, changes in proteolytic enzymes such as matrix metalloprotreinases

(MMPs), protein accumulation, and changes in the ECM are associated with anatomical
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changes in the heart (DeLeon-Pennell, Meschiari, Jung, & Lindsey, 2017; Frangogiannis,
2017; Lima et al., 2018; Spinale et al., 2016). Given the functional anatomical changes seen
in PTSD discusses above, the role of these ECM changes in the brain remains to be
elucidated, although animal models suggest involvement of these signaling cascades in brain
as well (Finnell et al., 2017).
Inflammation as a common mediator of PTSD and heart failure

A common biological cascade that is operative in most disease states, whereby PTSD and
HF are no exception, is inflammation. While this is a broad term and what specifically
defines inflammation is dependent upon location and context, there are common
inflammatory signaling systems that appear to be in common. In PTSD, elevated levels of
inflammatory markers like C reactive protein (CRP) and pro-inflammatory plasma
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cytokines, including interleukins (IL)-1, IL-6, tumor necrosis factor (TNF), as well as
decreased anti-inflammatory markers, have been found (Breen et al., 2018; Deslauriers et al.,
2017; Lindqvist et al., 2017; Z. Wang, Caughron, & Young, 2017), and the increased IL-6
and CRP have been shown to contribute to the increased CVD risk in PTSD (Boscarino,
2008). In advanced HF, an inflammtory cascade is similarly involed which can induce
proteases such as MMPs. There is a strong relationship between inflammation and MMPs,
as a number of MMPs proteolytically activate cytokines, chemokines, and growth factors
(Lindsey, 2018). For example, pro-IL-1 is biologically activated by MMP-9 (Schonbeck,
Mach, & Libby, 1998). Later, new ECM is produced by fibroblasts to form scar tissue.
Importantly, several studies have linked ANS dysregulation, seen in both PTSD and HF, to
alterations in the immune system and inflammation. For example, reduced HRV has been
associated with increased inflammatory markers (Frasure-Smith, Lesperance, Irwin, Talajic,
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& Pollock, 2009) in depression and CVD. Further, a growing body of literature has indicated
that parasympathetic activation via cholinergic activity inhibits inflammation, while
sympathetic activation leads to the increased release of inflammatory cytokines (Olofsson,
Rosas-Ballina, Levine, & Tracey, 2012; Tracey, 2007). In fact, cardiac arrest with cerebral
ischemia leads to microglial activation, proinflammatory cytokines and neural damage,
which also compromises the ability of the cholinergic anti-inflammatory pathway to contain
inflammation (Norman et al., 2011). These studies suggest that changes in different
pathways mediating inflammatory processes for heart failure and PTSD might be inter-
related, and interact via vagal afferent/efferent pathways and immune signaling. An
important consideration in investigating the intersection of PTSD and HF will be the role of
neuroinflammatory processes and microglial activation in the central nervous system, and
how these central changes modulate neural plasticity or synaptic reorganization that help
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drive peripheral changes including ANS dysfunction and/or peripheral immune markers [see
(Deslauriers et al., 2017)].
While activation of inflammatory pathways and the induction of proteases such as MMPS
occur in both PTSD and HF, how these can affect critical remodeling process such as
synaptic remodeling within the brain and ECM remodeling within the myocardium remains
to be explored. Several aspects of these common pathways also represent means of
communication, and feedback loops, between the heart and brain. As stress disorders, of

course the responses and feedback loops in the HPA axis are critical. But other points of
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communication include immune signaling as well as vagal efferents/afferents and the

autonomic nervous system. The latter provide links to the functional anatomical changes
seen in PTSD in regions controlling ANS function, such as the prefrontal cortex, amygdala,
and locus coeruleus. In addition, the circumventricular organs (CVOs) of the brain are a
specialized group of structures that lack a blood–brain barrier and are thus uniquely
positioned to monitor the systemic circulation (sensory CVOs) or being able to secrete
substances directly into the circulation (secretory CVOs)(Ferguson, 2014). Neurons
localized within the sensory CVOs are therefore ideally positioned at the blood–brain
interface to relay information from changes in systemic milieu to the brain. The CVOs thus
represent crucial gateways for body-to-brain communication. Of relevance to PTSD and
cardiovascular comorbidity, sensory CVOs such as the subfornical organ (SFO) and vascular
organ of the lamina terminalis (OVLT) have direct innervation to forebrain and hindbrain
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brain areas regulating stress, autonomic and emotional responses. The CVOs have been
shown to sense circulating concentrations of angiotensin II, sodium, calcium, as well as
osmolality, and they control a variety of autonomic outputs through efferent projections to
essential hypothalamic and medullary autonomic control centers, providing an avenue of
communicating peripheral changes in many mediators seen in Table 3 to the brain
(Ferguson, 2014). Finally, an additional means of communication are the extracellular
vesicles called exosomes, that have been implicated in cell-cell communication and
potentially various disease states, but their potential role in the comorbidities between PTSD
and HF remains unknown (Gill et al., 2018; Shanmuganathan, Vughs, Noseda, & Emanueli,
2018).
An example of a novel common mediator of PTSD and HF: The Orexin System
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An example of what might emerge as a novel therapeutic target from looking at

commonalities between PTSD and HF is the orexin system. The orexin/hypocretin
neuropeptides discovered in the late 1990s have a well-established role as a physiological
integrator in the control of sleeping and homeostatic regulation, as well as attention, arousal,
and stress responses (Berridge, Espana, & Vittoz, 2010; Carter, Schaich Borg, & de Lecea,
2009; Fadel & Burk, 2010; Flores, Saravia, Maldonado, & Berrendero, 2015; Mahler,
Moorman, Smith, James, & Aston-Jones, 2014; Sakurai, 2007). Two peptides, orexinA/
hypocretin1 [OxA] and orexinB/hypocretin2 [OxB] are produced by the preproorexin gene
by orexin neurons that are restricted to the hypothalamus but project throughout the central
nervous system, and the two G protein-coupled receptors (orexin/hypocretin 1 receptor
[Ox1R/HcrtR1], orexin 2 receptor [Ox2R/HcrtR2]) are found throughout the brain (Abreu,
Molosh, Johnson, & Shekhar, 2018; Fadel & Burk, 2010; Flores et al., 2015).
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The orexin system is well poised to impact the neural systems underlying the four PTSD
symptom clusters of re-experiencing, avoidance, negative cognitions and mood, and arousal/
reactivity, as well as the comorbidities of PTSD including sleep dysregulation, substance
abuse, and CVD. The orexin system modulates sleep, homeostatic regulation, arousal and
attention, but also fear learning and extinction (Abreu et al., 2018; Berridge et al., 2010;
Fadel & Burk, 2010; Flores et al., 2015; Mahler et al., 2014; Sakurai, 2007) as well as
reward and motivated behaviors, including food and drug seeking behaviors (Mahler et al.,

2014; Yeoh, Campbell, James, Graham, & Dayas, 2014). Studies have demonstrated low
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OxA levels in cerebrospinal fluid and plasma in PTSD patients compared to normal controls,
and a negative association between orexin concentrations and more severe symptoms in
these combat veterans with PTSD (Strawn et al., 2010). The positive correlation between
CSF and blood levels of orexin suggest this may also serve as a biomarker for PTSD (Strawn
et al., 2010). Preclinical studies have shown that intracerebroventricular administration of
OxA or OxB induces stress-like behavioral responses, activation of the HPA axis, and
cardiovascular responses associated with sympathetic activation (Abreu et al., 2018;
Berridge et al., 2010; Carrive, 2017). Pharmacological studies, studies using neurotoxic
lesions of the hypothalamus including orexin neurons, and studies in Ox1 or Ox2 knockout
mice all suggest a role for orexin in both the behavioral and cardiovascular responses during
fear learning and extinction (Carrive, 2017; Flores et al., 2015; T. Furlong & Carrive, 2007;
Sears et al., 2013; Soya & Sakurai, 2018), although unique roles for Ox1 and Ox2 receptors
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in different brain areas are seen. Interestingly, systemic administration of the dual Ox1R/
Ox2R antagonist almorexant decreased cardiovascular measures, but not the behavioral
responses during contextual fear (T. M. Furlong, Vianna, Liu, & Carrive, 2009).
The orexin system provides a provocative novel target and may provide a signaling pathway
that helps explain why some individuals are susceptible to traumatic stress, and others
remain resilient. While somewhere between 50 and 84% of the general population will
experience a traumatic event, estimates suggest that only around 10% of the population will
go on to develop PTSD (Goldstein et al., 2016; Kessler, Berglund, et al., 2005; Kessler,
Chiu, et al., 2005). Thus, a better understanding of individual differences in orexinergic
systems that lead to risk and resilience has implications for a variety of anxiety disorders,
but particularly PTSD and panic disorders (Abreu et al., 2018; Flores et al., 2015; Yeoh et
al., 2014). Divergent changes in the hypothalamic orexin system are associated with
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individual differences in behavioral fear extinction (Sharko, Fadel, Kaigler, & Wilson, 2017)
and CO2 -associated freezing (Monfils et al., 2018), plus the orexin system has been
implicated in mediating the PTSD-like symptoms in the susceptible population using two
different animal models of PTSD (S. Cohen et al., 2016; Grafe, Eacret, Dobkin, &
Bhatnagar, 2018). Interestingly, many of these effects of orexin on fear behaviors involve the
locus coeruleus, providing a link to neural systems controlling noradrenergic outputs and
sympathetic responses (Sears et al., 2013; Soya & Sakurai, 2018). Taken together,
modulation of orexin receptors (Abreu et al., 2018; Flores et al., 2015; Soya & Sakurai,
2018; Yeoh et al., 2014) and/or intranasal administration of orexinergic peptides (Calva,
Fayyaz, & Fadel, 2018) may represent a novel pharmacological approaches for PTSD.
Orexins also modulate cardiovascular functions, through both central autonomic control and
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peripheral actions. The extensive projections of orexin neurons to brainstem areas such as
the LC and rostral ventrolateral medulla (RVLM) anatomically support their role in the
central regulation of autonomic responses, especially cardiovascular responses to stress
(Carrive, 2017; Grimaldi, Silvani, Benarroch, & Cortelli, 2014) and sympathetic regulation
associated with chronic hypertension (Abreu et al., 2018). In a rat model of myocardial
infarction and progressive HFrEF, a significant reduction in orexin mRNA levels was
associated with the degree of cardiovascular compromise (Hayward et al., 2015), while in an
Ox2R deflicient transgenic mouse model cardiac function worsened with overstimulation of

the sympathetic or angiotensin receptor pathways (Perez et al., 2015). In human studies, a
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specific single nucleotide polymorphism (SNP) within the OxR2 was identified in HFrEF
patients (Perez et al., 2015). This orexin receptor gene variant was not only present in a
subset of HFrEF patients using GWAS, but more importantly, those HFrEF patients
appeared to be more refractory to conventional HF therapeutics. Further, higher OxA plasma
levels in HFrEF patients were associated with greater functional improvements following
conventional HF therapeutics when compared to HFrEF patients with low OxA plasma
levels (Ibrahim et al., 2016). These studies continue to provide support for the postulate that
a relative reduction in specific bioactive signaling pathways, such as that of orexin, can
potentially accelerate the HF process as well as influence response to HF therapeutics.
Like PTSD, these preclinical and clinical studies provide for some provocative questions and
new directions in terms of orexin in HF. Specifically, HF is a clinical syndrome and there are
distinct phenotypes of this disease which include HFrEF, but also HF with a preserved
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ejection fraction (HFpEF). In HFpEF, which may constitute up to 50% of overall HF

patients, whether and to what degree the SNP in the orexin receptor occurs and whether
orexin plasma levels are altered remains unexplored. In light of the fact that OxR2 gene
polymorphisms in HFrEF patients and transgenic ablation in mice were associated with HF
progression (Perez et al., 2015), then exploration of the effects of these orexin receptor
antagonists on cardiovascular outcomes may be warranted. Moreover, sleep disturbances
such as insomnia is not an infrequent symptom in patients with PTSD which also has been
shown to be associated with changes in orexin levels (Strawn et al., 2010). The positive
correlation between CSF and blood levels of orexin (OxA) suggest this may also serve as a
biomarker for PTSD and myocardial remodeling in HF patients (Ibrahim et al., 2016),
although it remains to be determined if there are genetic linkages between the orexin system
and PTSD, as in heart failure. Despite therapeutic issues with targeting single neuropeptide
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systems, identifying critical intersections and relationships of orexin signaling to that of HF

and PTSD syndromes would be an important translational and clinical research direction.
Recommendations for Future Research

The focus in this consortium on PTSD and CVD, but particularly HF, represents a distinct
perspective, because interconnections have not historically been combined in one evaluation.
Based on the existing comorbidity of PTSD and HF, particularly within the VA health
system, the VA sponsored consortium identified several specific common systems that are
dysregulated in both PTSD and HF, resulting in a synergistic acceleration and amplification
of both disease processes. Further, we developed recommendations for further exploration of
provocative new research directions and therapeutic targets, described below. These
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postulates are intended to help guide policy makers and/or funding agencies, as well as the
research communities focused on PTSD and HF, to identify and bridge gaps in knowledge
and further our understanding of the common mediators between these comorbid conditions,
as well as identify novel therapeutic approaches.

Postulate One
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Since PTSD accelerates/exacerbates HF and vice-versa, studies are needed to further explore
the comorbidities between PTSD and HF. 1) Use Big Data approaches to define relative risk
between PTSD and HF, including distinguishing PTSD comorbidity in patients with HFpEF
vs. HFrEF. Studies are needed to examine if patients with PTSD (especially Veterans) have
worse outcomes with HF, plus the factors contributing to PTSD symptoms in patients with
CVD in general and HF in particular. The VA system in general, the Million Veteran
Program, and VINCI represent excellent opportunities in this domain. One example is use of
Mendelian randomization approaches with existing GWAS data in HF and PTSD
populations. 2) Since an earlier cardiovascular event (such as MI) could serve as the
traumatic stressor for HF and/or PTSD, additional studies expanding the heart-to-brain
connection are needed. Such studies could explore if treatments for HF improve PTSD
symptomology, and if sensory afferent and/or interoceptive mechanisms or the common
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pathways mentioned above are involved in the impact of HF treatments on PTSD. 3) Use
imaging studies (both existing databases and prospective new studies) to better examine the
relationship between HF and PTSD, 4) Enhance human studies through adding relatively
simple cardiovascular measures to PTSD studies and basic PTSD assessments to HF studies.
This approach would require more synergistic research teams combining cardiovascular and
psychiatric expertise in large-scale clinical studies. 5) Enhance existing and develop new
animal models to assess PTSD-like and HF phenotypes to further explore the common
mediators between cardiovascular and behavioral phenotypes. These models will be
important for determining common causation and identifying and testing novel therapeutic
targets for comorbid PTSD and HF. Animal models would also be useful for exploring the
impact of prior cardiovascular events on PTSD-like symptoms as well as cardiovascular
changes due to traumatic stress.
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Postulate Two
Since concordant autonomic dysfunction occurs in PTSD and HF, studies are needed to
explore if autonomic dysfunction plays a causative role in the comorbidity between PTSD
and HF. 1) Determining the causative links between altered heart rate variability, diminished
parasympathetic tone, and enhanced sympathetic tone in PTSD with HF. Ascertain the most
informative correlations between ANS changes in heart and brain in patients with PTSD and
HF, or in animal models of PTSD or HF. 2) Human-based and preclinical studies using
interventions like autonomic nervous system stimulation to alter the balance between
sympathetic and parasympathetic processes in PTSD and HF. 3) Studies interrogating the
progression of autonomic dysfunction in both PTSD and HF in clinical and pre-clinical
populations.
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Postulate Three
Examine the role of sleep dysregulation in PTSD and HF. 1) Studies evaluating if sleep
dysregulation is a result or a cause of autonomic dysfunction, and if sleep dysregulation is
one common mediator of the PTSD-HF comorbidity. 2) Studies elucidating if sleep
dysregulation emerges after patients develop these conditions, or if sleep dysregulation

predicts susceptibility to PTSD or HF. 3) Studies examining orexin as a key player in the
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connections between sleep dysregulation, PTSD, and HF.
Postulate Four
Common cellular, inflammatory, and signaling pathways exist in both PTSD and HF, thus
studies are needed to explore specific mediators of PTSD and HF, with the goal of
identifying new therapeutic targets. 1) Studies identifying and exploiting common signaling
cascades and molecules as interventional strategies in PTSD and HF. An example is the
orexin/hypocretin system. 2) Studies modifying the common inflammatory pathways, such
as MMP-9, IL-1β and TGF, to determine whether there is an overlapping therapeutic
strategy for treating patients with both HF and PTSD. A key question is if systemic
inflammation is needed for adverse changes in the brain and heart. 3) The renin-angiotensin
system (RAS) is a common initiator for inflammation and behavioral changes, so is there a
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link between RAS-induced heart and brain inflammation and is this a therapeutic
opportunity? 4) Studies determining the role of common changes in ECM, plaque formation,
and tissue/synapse remodeling in PTSD and HF. 5) Studies exploring the role of points of
communication and feedback loops between heart and brain in the progression of PTSD and
HF. What is the role of vagal efferents/afferents in PTSD and HF? Are the circumventricular
organs or exosomes novel approaches for therapeutic strategies? 6) Develop new imaging
paradigms that can detect protein buildup (such as plaques), remodeling, and common
mediators in patients with both PTSD and HF.
Postulate Five
Common modifiers exist in PTSD and HF progression that remain to be explored. 1) Studies
examining the influence of age in PTSD and HF. How does age independently influence
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PTSD and HF progression, and their comorbidity? Are both PTSD and HF related to
accelerated aging processes as a common mediator? 2) What are the influences of gender
and gonadal hormones in the comorbidity and progression of PTSD and HF? 3) Many of the
common mediators are impacted by obesity, diabetes and metabolic disorders, so how do
these conditions influence PTSD and HF?
Importantly for the field, many similar recommendations were recently posted from a
workshop on “The Cardiovascular Consequences of Post-Traumatic Stress Disorder,”
sponsored by the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Maryland
from November 13–14, 2018. See: https://www.nhlbi.nih.gov/events/2018/nhlbi-working-
group-cardiovascular-consequences-post-traumatic-stress-disorder
ACKNOWLEDGEMENTS
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We would like to thank Dr. Victoria Macht Preston for constructing the figure. Support for the meeting provided
through a BLRD Veterans Administration Field Meeting Proposal awarded to the William Jennings Bryan Dorn VA
Medicine Center (now the Columbia VA Health Care System, Columbia, SC). Support to MAW from VA Merit
Awards I01 BX001374, IO1 BX001804 and I21 BX002085. Support to MLL from VA Merit Award 5I01BX000505
and from NIH HL075360, HL129823, and HL137319. Support to VBR by VA Merit Award BX004312, NIAAA
AA026560 and the VA Center of Excellence for Stress and Mental Health. Support to RS from VA Merit award
2I01BX001075. Support to SKW from VA Award I21 BX002085 and BX001374 and from NIH MH113892 and
American Heart Association 15SDG224300017. Support to FS from VA Merit 2I01-BX000168 and NIH
R01HL130972.

CONFLICT of INTERESTS/DISCLOSURES
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Israel Liberzon – no COI to report. Government grants NIH, DoD, foundation grants – Cohen Veterans Bioscience,
Industry: – Sunovion Inc, ARMGO Pharm. Inc. None is related to cardiovascular/PTSD comorbidity.
Abbreviations
ANS Autonomic nervous system
CDI Coronary distensibility index
CPAP Continuous positive airway pressure
CRF Corticotropin releasing factor
CRP C reactive protein

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CSA Central sleep apnea
CVD Cardiovascular disease
CVO Circumventricular organs
dACC Dorsal anterior cingulate cortex
DMV Dorsal motor nucleus of the vagus
ECM Extracellular matrix
ECM Extracellular matrix
GWAS Genome-wide association study

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HF Heart failure
HFpEF Heart failure with preserved ejection fraction
HFrEF Heart failure with reduced ejection fraction
HPA Hypothalamic-pituitary-adrenal
HRV Heart rate variability
IL Interleukin
LC Locus coeruleus
LV Left ventricular
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MI Myocardial infarction
MMP Matrix metalloproteinase
NE Norepinephrine
OEF Operation Enduring Freedom

OIF Operation Iraqi Freedom

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OVLT Organ of the lamina terminalis
Ox1R/HcrtR1 Orexin/hypocretin 1 receptor
Ox2R/HcrtR2 Orexin/hypocretin 2 receptor
OxA OrexinA/hypocretin1
OxB OrexinB/hypocretin2
PNS Parasympathetic nervous system
PTSD Post-traumatic stress disorder
RSA Respiratory sinus arrhythmia

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RVLM Rostral ventrolateral medulla
SAVE Sleep Apnea Cardiovascular Endpoints
SFO Subfornical organ
SNP Single nucleotide polymorphism
SNS Sympathetic nervous system
SPS Single prolonged stress
TNF Tumor necrosis factor

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VA Veterans Administration
vmPFC Ventral medial prefrontal cortex
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Figure 1: Mediators and modulators of the co-morbidity between PTSD and heart failure.
Diagram shows that stress, such as experiences during combat, influences multiple systems
in the brain and heart that can serve to induce PTSD as well as cardiovascular diseases.
Mounting evidence suggests that the co-morbidities between PTSD and heart failure might
be due to similar autonomic nervous system dysregulation, similar genetic polymorphisms,
and/or common changes in cell signaling, communication and remodeling, plus immune
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dysregulation. Sleep dysregulation, gender, aging and metabolic disorders can all modify the
severity and progression of PTSD and heart failure symptoms, but it is yet unknown how
these modifiers contribute to the comorbidity between PTSD and heard failure.
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TABLE 1:
Attendees at Cardiovascular Comorbidities in PTSD: The Brain-Heart Consortium

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Michael Burgio (Scientific Program Manager ORD, Department of Veterans Affairs)
K. Sue Haddock, PhD, ACOS Dorn VAMC (Organizer)
Marlene Wilson, PhD [Health Research Scientist, Dorn VAMC, Univ South Carolina School of Medicine Columbia SC] (Organizer)
Israel Liberzon, MD, PhD [previously Chief of Mental Health Service, Ann Arbor VAMC; co-Director Trauma, Stress and Anxiety Research
Group, University of Michigan]
Frank Spinale, MD, PhD [Clinical Investigator, Dorn VAMC, Columbia SC; Professor, Univ South Carolina School of Medicine]
Victoria Risbrough, Ph.D. [Associate Director of Neuroscience, Center of Excellence for Stress and Mental Health VA San Diego Healthcare
System]
Michael Zile, MD [Director, Medical Intensive Care Unit, Ralph H. Johnson (Charleston) VAMC]
Renu Sah, PhD [Research Scientist, Cincinnati VAMC; University of Cincinnati]
Amy Bradshaw, PhD [Gazes Cardiac Research Institute, Ralph H. Johnson (Charleston) VAMC]:
Merry Lindsey, PhD [Research Health Scientist, Research Service G.V. (Sonny) Montgomery VAMC and Professor, University of Mississippi
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Medical Center]
John Williamson, PhD [University of Florida, McKnight Brain Institute Gainesville, FL (VA)]
Eric Porges [Center for Cognitive Aging & Memory (CAM); Department of Clinical and Health Psychology, Univ Florida, Gainesville]
Susan Wood, PhD [Univ South Carolina School of Medicine; Dorn VAMC]:
David Diamond, PhD [Director, University of South Florida Center for Preclinical and Clinical Research on PTSD, retired from Tampa VA]
Frederica Del Monte [Associate Professor of Medicine; Medical University of South Carolina (MUSC)]
Wayne Carver [Univ South Carolina School of Medicine]
Kurt Barringhaus [Dorn VAMC, Palmetto Health Richland]
Justin Gass [Medical University of South Carolina (MUSC)]
Mohamad Azhar [Univ South Carolina School of Medicine]
Jim Fadel [Univ South Carolina School of Medicine]

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Kathy Mason [Dorn VAMC, Univ South Carolina School of Medicine]
Daping Fan [Univ South Carolina School of Medicine]
Jacqueline McGinty [Medical University of South Carolina (MUSC)]
Jay (Jack) Ginsberg [Dorn VAMC]
NOTE: affiliations listed were at the time of the meeting, July 2017
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Table 2:
Potential cardiovascular-related phenotypes in animal models of PTSD

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Model Changes in HPA axis Inflammation Sleep disturbances Cardiovascular

functioning abnormalities
Inescapable Plasma: ↑ CORT/ACTH Plasma: ND ↑ startled awakening Sensitized BP response to

foot shocks (; ↑ feedback-DST; ↑ Brain: ↑ microglial activation (9 (3 wks); ↓↑REM (3 footshock (Bruijnzeel et al.,
CORT in response to the wks); ↑ pro-inflammatory cytokines wks); ↑ total 2001)
situational reminder (2 (TNF-α, IL-6, IL-12); ↑ TLR4 levels; wakefulness and ↑ sensitivity to catecholamine
wks) ↑ NLRP3 levels NREM time (1–8 stimulation in myocytes
Brain: ND wks) (Penna & Bassani, 2010)
Predator Plasma: ↑ CORT/ACTH Plasma: ND ND ↑ HR, ↓ HRV (Koresh et al.,

scent/stress (9 days); ↑ feedback- Brain: ↑ pro-inflammatory cytokines 2016)
DST (IL-1β, IL-18, TNF-α) and NLRP3 ↓ decreased coronary tone
Brain: ↑ GR (9 days); levels; ↑ TLR4 levels; ↓ anti- (Lazuko et al., 2018);
inflammatory cytokine IL-10 (4 wks) ↑ myocardial sensitivity to
ischemic injury (Rorabaugh et
al., 2015)
↑ BP (Zoladz & Diamond,
2016)
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Single Plasma: ↑ feedback-DST Plasma: ND Altered REM- Increased apoptosis in

prolonged (1 wk); ↑ CORT(bl) and Brain:↑microglia,↑pro-inflammatory NREM and EEG cardiomyocytes (Liu et al.,
stress ACTH(bl) cytokines (TNF-α, IL-1β) (1–2wk) bands (1 wk) 2016)
Brain: ↑ GR (1 wk);
IMO/ Plasma: ↓ and ↑ACTH/ Plasma: ND ↑ REM (1 day) Altered beta receptor
Restraint CORT for homo- and Brain: ND signaling in heart (Laukova et
stress heterotypic stressors, al., 2014)
respectively (1–4 wks); ↑ Altered baroreflex; ↑ HR
feedback-CORTrec (18 (Vieira et al., 2018)
days)
Brain: ND
CVS Plasma: ↑ CORT(bl)/ Plasma: ↑ pro-inflammatory ↑ wake state and ↓ Altered baroreflex; ↑ HR
ACTH(bl); ↓ CORT/ cytokines (IL-1β, IL-6, TNF-α); ↓ REM sleep ); “shift” (Vieira et al., 2018)
ACTH hetero-response anti-inflammatory cytokine IL-10 of activity rhythms
(3 wks); ↑ feedback- Brain: ↑ pro-inflammatory cytokines (more and less
DST (IL-1β, IL-6, TNF-α); ↑ TLR2 and active during light
Brain: ↑ GR- and MR- NLRP3 levels; ↑ microglial and dark phases,
positive neurons (2 activation; ↓ anti-inflammatory respectively)
days); cytokine IL-10
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Social defeat Plasma: ↑CORT(bl) (12 Plasma: ↑ pro-inflammatory ↓ REM; ↑ NREM Ventricle fibrosis and altered
days); ↑ACTH(bl); ↓ cytokines (IL-1β, IL-6, TNF-α) (6 (1–28 days) myocardial electrical stability
feedback-DST days) (Carnevali et al., 2013)
Brain: ↑ pro-inflammatory cytokines ↑ BP, ↑ HR, arrhythmias
(IL-1β, IL-6, TNF-α) and microglial (Finnell et al., 2017; Finnell
activation (6 days) et al., 2018)
References for HPA, Immune and sleep disruptions in PTSD animal models: see (Deslauriers et al., 2018).
ND: Not Determined:
Abbreviations: ACTH, adrenocorticotropic hormone; ACTH(bl); adrenocorticotropic hormone at baseline; Amy, amygdala; CORT, corticosterone;
CORT(bl), baseline corticosterone; CORTrec; CORT recovery is faster; DST, dexamethasone suppression test; EEG, electroencephalography; GR,
glucocorticoid receptor; heterotypic stressor, other stressor; homotypic, /heterotypic stressor, same stressor; HP, hippocampus; HPA, hypothalamic-
pituitary-adrenal; IL-1β, interleukin-1β; IL-10, interleukin-10; IL-12, interleukin-12; IL-18, interleukin-18; IL-6, interleukin-6; LTP/LTD, long-
term potentiation/depression; MD, mean diffusivity; MR, mineralocorticoid receptor; NREM, non-rapid eye movement; PFC, prefrontal cortex;
REM, rapid eye movement; TLR2, toll-like receptor 2; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; UVS, unpredictable variable
stress.
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Table 3.
Common mediators between PTSD and Heart Failure: Cell signaling, communication and remodeling
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System Dysregulated Common Mediators

Autonomic nervous system Sympathetic/Parasympathetic Imbalance
Adrenergic system Catecholamines- Epinephrine, Norepinephrine, Dopamine, and Adrenergic receptors (α and
β)
Cholinergic system: Acetylcholine and cholinergic receptors (muscarinic, nicotinic)
Hypothalamic-Pituitary-Adrenal (HPA) System Glucocorticoids, glucocorticoid receptors, mineralocorticoid receptors, corticotropin-

releasing factor
Renin-Angiotensin System Angiotensin II, renin, angiotensin converting enzyme Angiotensin receptor type 1 (AT1)
Endocannabinoids AEA, 2AG, CB1, CB2 receptors
Inflammation and immune factors Pro-inflammatory: (IL-1β, IL-6, tumor necrosis factor (TNF), α, c reactive protein) Anti-
inflammatory: (IL-4, IL-10, TNF) Macrophages or Microglia
Peptides Atriuretic peptides, adrenomedullin, endothelin, orexin, neuropeptide Y, corticotropin

releasing factor
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Proteolytic enzymes and protein accumulation Matrix metalloproteinases (MMPs) & Tissue inhibitor of Metalloproteinases (TIMPS)-
MMP-9 & TIMP-1 A disintegrin and metalloproteinases with & without thrombospondin
motifs
Response to hypoxia/ ischemia, acid-base Reactive oxygen species signaling, hypoxia inducible factors
disturbance, oxidative stress
Remodeling and Extracellular Matrix (ECM) Collagens, laminin, fibronectin, integrins, matricellular proteins
changes
For references see: (Boscarino, 2004; Brudey et al., 2015; Eraly et al., 2014; Gill et al., 2008; Hill et al., 2018; Miller et al., 2011; Pacher et al.,
2018; Spinale et al., 2016; von Kanel, Begre, et al., 2010; von Kanel, Schmid, et al., 2010)
Abbreviations: AEA: N-arachidonoyl ethanolamine (anandamide); 2AG (2-arachidonoyl glycerol)
Note: For more information, please refer to citations provided in text.

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TABLE 4:
Genetic polymorphisms that may confer vulnerability to PTSD and CVD: Evidence from gene variant
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association studies or links to disease endophenotypes
Gene (polymorphism) Biological Effect PTSD Risk (Group) CVD Risk (Group) References
ACE(I/D, rs4311) ↑ ACE angiotensin ↑ (rs 4311 T allele ↑ (I/D D allele carriers) (Nylocks et al., 2015;
levels carriers) Raynolds et al., 1993)
COMT (Val158Met) ↓ Lower COMT High ↑ (Met/Met carriers) ↑ (Met/Met carriers) (Deslauriers, Acheson, et al.,
dopamine 2018; Mir et al., 2018)
AGT (T174M M235T) ↑ Angiotensin levels ? (Links to stress) ↑ (M235T T carriers) (Winkelmann et al., 1999)
AT1R (A1166C) ↑ Angiotensin ? (Links to fear memory ↑ C allele carriers (Cameron et al., 2006; Wu et
receptor signaling and stress) al., 2009)
ADRA2B Glu301- ↑ Adrenergic ↑ (Glu301-Glu303 ↑ Glu301-Glu303 variants (Laukkanen et al., 2009;

Glu303deletion variants signaling Variants) Liberzon et al., 2014; Snapir
et al., 2003)
5-HTTLPR (SLC6A4) ↓ 5-HT transporter ↑ (L(A) allele carriers) ? (Links to cardiovascular (Grabe et al., 2009; Way &
function reactivity to stress) Taylor, 2011)
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NET (SLC6A2) ↓ norepinephrine ↓ norepinephrine ↓ norepinephrine (Marques et al., 2017; Pietrzak

(rs7194256; s2242446) transporter function transporter availability transporter function et al., 2015)
FKBP5 (rs1360780; ↓ Glucocorticoid ↑ (T allele carriers) ? methylation and early (Lebois et al., 2016; Lovallo et
rs9296158) signaling life stress-cardiometabolic al., 2016)
risk)
BDNF rs6265 ↓ BDNF ↑ Met/Met carriers ↑ Val/Val carriers (Jiang et al., 2017; Lebois et
(Val66Met) al., 2016; Mehta et al., 2018)
↑=Increase ↓=Decrease? Potential links, however, a direct association not demonstrated
Abbreviations: ACE: angiotensin converting enzyme; ADRA2B: Alpha 2B adrenergic receptor; AGT: angiotensinogen AT1R: angiotensin II
receptor type 1; BDNF: Brain derived neurotrophic factor; COMT: catechol-O-methyltransferase; 5-HTTLPR: 5-HT (serotonin) transporter-linked
polymorphic region; NET: Norepinephrine transporter; FKBP5 FK506-binding protein 51, I/D insertion/deletion
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Published in final edited form as:

Common pathways and communication between the Brain and

In addition to PTSD-associated risks in developing CVD, the manifestation of CVD can in

Stress. Author manuscript; available in PMC 2020 September 01.

neurophysiologically regulated systems may reflect and/or influence changes in

Section 1. Symptoms and Etiology

Stress. Author manuscript; available in PMC 2020 September 01.

negative cognitions and mood, and arousal/reactivity. Re-experiencing refers to having

spontaneous memories, recurrent dreams, or flashbacks of the traumatic event, or

Brain systems involved in PTSD

towards threat and, consequently, exaggerated threat detection, manifested in increased

Stress. Author manuscript; available in PMC 2020 September 01.

Animal Models of PTSD

Stress. Author manuscript; available in PMC 2020 September 01.

HF Definition and Relation to PTSD

Stress. Author manuscript; available in PMC 2020 September 01.

While HF is due to impairments in LV functional performance, this results in systemic

symptoms of HF include confusion, sleep disorders, dizziness, altered mood, and

AMP formation is a common feature of cardiomyocyte responses to stress. While increased

Animal Models of Heart Failure

Stress. Author manuscript; available in PMC 2020 September 01.

Section 2: Autonomic nervous system (ANS) in PTSD and HF

neurophysiological regulation of emotion seen in PTSD may manifest as anger or depression

Stress. Author manuscript; available in PMC 2020 September 01.

Hyperarousal Features of Sleep and Autonomic Imbalance in PTSD and HF

Common complaints in patients with PTSD include nightmares, distressed awakenings,

Stress. Author manuscript; available in PMC 2020 September 01.

in mean arterial pressure in comparison to wakefulness, and a lack of reduction in mean

Stress. Author manuscript; available in PMC 2020 September 01.

Section 3. Parallel Cell Signaling Pathways in PTSD and HF

Stress. Author manuscript; available in PMC 2020 September 01.

Inflammation as a common mediator of PTSD and heart failure

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communication include immune signaling as well as vagal efferents/afferents and the

An example of what might emerge as a novel therapeutic target from looking at

Stress. Author manuscript; available in PMC 2020 September 01.

Stress. Author manuscript; available in PMC 2020 September 01.

ejection fraction (HFpEF). In HFpEF, which may constitute up to 50% of overall HF

systems, identifying critical intersections and relationships of orexin signaling to that of HF

Recommendations for Future Research

Stress. Author manuscript; available in PMC 2020 September 01.

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connections between sleep dysregulation, PTSD, and HF.

Stress. Author manuscript; available in PMC 2020 September 01.

CDI Coronary distensibility index

CPAP Continuous positive airway pressure

CRF Corticotropin releasing factor

CRP C reactive protein

CSA Central sleep apnea

CVD Cardiovascular disease

CVO Circumventricular organs

dACC Dorsal anterior cingulate cortex

DMV Dorsal motor nucleus of the vagus

ECM Extracellular matrix

ECM Extracellular matrix

GWAS Genome-wide association study

HFpEF Heart failure with preserved ejection fraction

HFrEF Heart failure with reduced ejection fraction

HRV Heart rate variability

MMP Matrix metalloproteinase

OEF Operation Enduring Freedom

Stress. Author manuscript; available in PMC 2020 September 01.