Introduction Both trauma exposure and post-traumatic stress disorder (PTSD) are associated with increased risk of cardiovascular disease (CVD), the leading cause of death in the USA. Endothelial dysfunction, a modifiable, early marker of CVD risk, may represent a physiological mechanism underlying this association. This mechanism-focused cohort study aims to investigate the relationship between PTSD (both in terms of diagnosis and underlying symptom dimensions) and endothelial dysfunction in a diverse, community-based sample of adult men and women.
Methods and analysis Using a cohort design, 160 trauma-exposed participants without a history of CVD are designated to the PTSD group (n=80) or trauma-exposed matched control group (n=80) after a baseline diagnostic interview assessment. Participants in the PTSD group have a current (past month) diagnosis of PTSD, whereas those in the control group have a history of trauma but no current or past psychiatric diagnoses. Endothelial dysfunction is assessed via flow-mediated vasodilation of the brachial artery and circulating levels of endothelial cell-derived microparticles. Two higher order symptom dimensions of PTSD—fear and dysphoria—are measured objectively with a fear conditioning paradigm and attention allocation task, respectively. Autonomic imbalance, inflammation, and oxidative stress are additionally assessed and will be examined as potential pathway variables linking PTSD and its dimensions with endothelial dysfunction. Participants are invited to return for a 2-year follow-up visit to reassess PTSD and its dimensions and endothelial dysfunction in order to investigate longitudinal associations.
Ethics and dissemination This study is conducted in compliance with the Helsinki Declaration and University of California, Los Angeles Institutional Review Board. The results of this study will be disseminated via articles in peer-reviewed journals and presentations at academic conferences and to community partners.
Trial registration number NCT03778307; pre-results.
- anxiety disorders
- adult psychiatry
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Strengths and limitations of this study
This is the first study to assess endothelial dysfunction, an early marker of cardiovascular disease risk, using both functional (flow-mediated vasodilation) and cellular (endothelial cell-derived microparticle) approaches in a sample of trauma-exposed individuals.
This study is the first to investigate whether post-traumatic stress disorder (PTSD) and its dimensions are related to change in endothelial dysfunction over time.
This study comprehensively examines whether objective measures of underlying dimensions of PTSD—fear and dysphoria—are related to endothelial dysfunction.
Whereas previous research on PTSD and endothelial dysfunction has been conducted in predominantly male samples of veterans and police officers, we have a diverse, community-based sample of men and women with and without current PTSD who have been exposed to a range of traumas.
Although the approach of assessing key constructs in the research laboratory permits more controlled measures of these constructs, it limits the generalisability of findings to participants’ experiences in real-world settings.
Despite advances in prevention and intervention, cardiovascular disease (CVD) remains the leading cause of death in the USA.1 Growing research demonstrates longitudinal links between trauma exposure, post-traumatic stress disorder (PTSD) and CVD, suggesting trauma and PTSD as novel targets for reducing CVD risk. Trauma is common; the vast majority of individuals (50%–90%) experience a trauma in their lifetime, including natural disasters, physical assault and unwanted sexual contact.2 3 PTSD is the quintessential trauma-related disorder, characterised by symptoms of re-experiencing of the trauma, avoidance of trauma reminders, negative alterations in cognition and mood, and hyperarousal.4 PTSD has been associated with heightened risk of incident CVD, even after accounting for numerous risk factors.5–11 Trauma exposure, independent of trauma-related psychopathology, has also been linked to elevated CVD risk.5 12–14
Given this evidence, experts in clinical psychology and cardiology have called for CVD risk surveillance after trauma.15 To support such efforts, it is critical to identify intermediary mechanisms linking post-traumatic stress and CVD risk that can guide monitoring and intervention approaches. Endothelial dysfunction may be one such mechanism. Endothelial cells, which form the inner lining of blood vessels, are one of the first physiological indicators of reduced capacity to respond to cardiovascular demand, with endothelial dysfunction implicated in the pathophysiology of atherosclerosis and CVD.16 17 For every 1% decrease in brachial artery flow-mediated vasodilation (FMD; a functional measure of endothelial dysfunction), CVD risk increases by 9%–13%.18–20 Endothelial dysfunction can also be assessed by quantifying circulating levels of endothelial cell-derived microparticles (EMPs), direct measures of endothelial cell injury involved in atherosclerosis risk.21–24 As endothelial dysfunction can be detected in CVD-free individuals25 and is a malleable risk marker responsive to intervention,26 27 it is an optimal target for prevention and risk mechanism research.
Initial studies in select samples (women aged 40–60 years, male veterans or police officers) suggest that trauma exposure and elevated PTSD symptoms are associated with lower FMD.28–30 Additionally, work in trauma-exposed individuals reveals that the greater the PTSD symptom severity, the lower the FMD, even among individuals without PTSD diagnoses.28 PTSD has also been associated with biomarkers of endothelial dysfunction,31 32 although no studies have considered specific markers of cellular injury (EMPs).
Existing research has also been limited by treating PTSD as a homogeneous diagnosis. However, PTSD has great heterogeneity in how symptoms manifest.33 Thus, understanding which aspects of PTSD particularly affect intermediary mechanisms will inform monitoring efforts and intervention development. Broadly, PTSD consists of two higher order dimensions: fear and dysphoria.34–36 Fear reflects an alarm response to perceived danger, whereas dysphoria represents low positive affect and anhedonia.34 PTSD dimensions hold promise for distinguishing specific versus non-specific aspects of the disorder.34 Whereas dysphoria is considered an auxiliary component of PTSD, shared with depression, fear is considered a core component of PTSD.37 Longitudinal network analyses indicate that fear responses are central aspects of acute and chronic post-traumatic stress responses, whereas dysphoria symptoms are secondary responses that develop over time.35 Furthermore, impaired fear learning and inabilities to suppress fear in safe situations are key pathological processes in PTSD.38 Experimentally, fear conditioning paradigms provide a translational framework for examining dysregulated fear responses,39 which can be measured using objective psychophysiological measures, including skin conductance (SC) responses and fear-potentiated startle (FPS).40–42 In fear conditioning research, PTSD has been characterised by psychophysiological responses indicative of dysregulated fear responding, including difficulties with safety signal processing and fear inhibition.43–45 Additionally, some trauma-exposed individuals without PTSD exhibit psychophysiological responses akin to individuals with PTSD,46 47 reflecting similar trauma-related psychophysiological fear that could explain their lower FMD.28
Furthermore, psychophysiological fear responses are promising targets for understanding links between PTSD and CVD risk, as they may engage key biological mechanisms. For example, repeated bouts of psychophysiological reactivity may promote autonomic dysregulation48–50 and elevated systemic inflammation and oxidative stress,51–53 which can have deleterious effects on cardiovascular health.54 However, research has yet to comprehensively examine mechanisms by which psychophysiological fear—or another PTSD dimension—may relate to endothelial dysfunction.
This study examines links between PTSD and its dimensions with endothelial dysfunction in trauma-exposed men and women (see figure 1 for conceptual model). First, we examine the association of PTSD diagnosis with endothelial dysfunction, assessed via functional (FMD) and cellular (EMP) measures. We hypothesise that participants with versus without PTSD will have lower FMD and, secondarily, higher EMP levels. Second, we investigate which PTSD dimensions are most strongly associated with endothelial dysfunction. We predict that stronger psychophysiological fear responses (measured by FPS and SC) will be associated with lower FMD and, secondarily, higher EMP levels. Although we focus on the core dimension of fear, we investigate the dysphoria–endothelial dysfunction relation to comprehensively assess potential intervention targets. Third, we explore autonomic imbalance, inflammation and oxidative stress as potential mechanisms. Finally, we examine whether PTSD and its dimensions predict change in endothelial dysfunction over 2 years.
Methods and analysis
Brief study overview
This mechanism-focused cohort study examines primarily cross-sectional and, secondarily longitudinal, associations. Enrolment began in 2019, and the study is projected to continue through 2023. Investigating the PTSD diagnosis–endothelial dysfunction relation uses a case–control approach, whereas analyses of PTSD dimensions are conducted in the full sample. The sample will include 160 men and women without CVD from the Los Angeles area (80 individuals with PTSD; 80 trauma-exposed controls). Group designations are determined via diagnostic interview assessment. No-trauma controls were not included, as this study focuses on identifying what aspects of PTSD symptoms are linked to endothelial dysfunction.
Eligible participants are >18 years old, fluent English speakers and trauma-exposed. Participants in the PTSD group have a current PTSD diagnosis based on the past-month Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (CAPS-5),55 whereas controls are trauma exposed with no psychiatric diagnoses and a CAPS-5 score <25.56 Exclusions include (a) individual CVD history (physician-diagnosed myocardial infarction, angina, heart failure, peripheral artery disease, stroke, transient ischaemic attack, atrial fibrillation, ventricular arrhythmias); (b) current psychotropic medication use (except benzodiazepines taken as needed), as this has been shown to influence key study variables including FMD, psychophysiological responses and attentional allocation57–61; (c) current bipolar, psychotic, or moderate or severe substance use disorder; (d) mild or severe cognitive impairment (Mini-Mental State Examination (MMSE) score <18)62; (e) acute, unstable, or severe medical disorder or pregnancy; or (f) needing immediate psychiatric intervention (eg, active suicidality).
Recruitment and enrolment
The study timeline is depicted in figure 2. Participants are recruited via online advertisements, University of California, Los Angeles (UCLA) staff listservs, flyers throughout the community and word-of-mouth referrals. Interested individuals are phone screened to assess initial eligibility. After obtaining verbal consent, research personnel assess inclusion and exclusion criteria: English fluency, CVD history, psychotropic medication use, lifetime exposure to 17 types of trauma (using the Life Events Checklist for DSM-5),63 and past-month PTSD symptoms with respect to the trauma participants identify as most distressing (using the PTSD Checklist for DSM-5 (PCL-5)).64 The most distressing trauma is categorised as combat, non-combat interpersonal violence (eg, assault) or non-interpersonal violence (eg, accident).65 Time since trauma is also recorded. Eligible individuals are scheduled for a diagnostic interview assessment.
Diagnostic interview assessment
Highly trained research personnel administer standardised clinical interviews. Interviewers have at least a Bachelor’s degree and complete extensive training including self-guided study, didactics, diagnosing cases from recordings and role-playing. After obtaining written informed consent, the interviewer conducts a brief clinical interview to build rapport and review information about the participant’s history and current functioning.
The first diagnostic interview administered is the CAPS-5,55 a gold standard structured interview querying past-month experiences of the 20 DSM-5 PTSD criteria.66 Symptoms are anchored to an index trauma self-identified by participants as their most distressing event. Responses for each symptom are scored with respect to frequency and intensity and combined into a severity score ranging from 0 (absent) to 4 (extreme/incapacitating). Symptom endorsement is used to determine current PTSD diagnosis, and severity scores are summed for a total severity score. Presence and history of other psychopathology are evaluated using the Structured Clinical Interview for DSM-5, Research Version,67 the gold standard in psychopathology assessment. Mood disorder episodes and psychotic symptoms are assessed for all participants; anxiety, substance abuse, eating and obsessive-compulsive disorders are assessed as needed based on screening questions. Interviewers then assess participants’ medical history and health behaviours, including family history of CVD, personal history of medical conditions, pregnancy, medications, smoking and physical activity. If cognitive impairment is suspected, the MMSE is administered.62
Participants conclude the visit by completing several valid and reliable questionnaires. After reporting on sociodemographics, participants complete measures of childhood adversity: the Childhood Trauma Questionnaire68 (measuring child abuse and neglect); the Childhood Experiences of Care and Abuse69 antipathy and neglect items (anchored to participants’ primary caregiver); the Conflict Tactics Scale70 (measuring family violence); and a food insecurity measure based on the US Department of Agriculture’s Food Security Scale.71 Participants report on PTSD symptoms (anchored to the CAPS-5 index trauma) using the PCL-564 72 and depressive symptoms using the Patient Health Questionnaire-8.73 Participants describe their sleep with the Pittsburgh Sleep Quality Index (PSQI),74 PSQI Addendum for PTSD,75 Insomnia Severity Index76 and RU-SATED scale.77
Propensity scores are used in recruitment to improve the balance of sociodemographic and trauma-related characteristics across the PTSD and trauma-exposed control groups.78 Scores reflecting propensity of PTSD group membership are calculated using age, gender, race/ethnicity, trauma type, time since trauma and two-way interactions among these variables. Matching during recruitment is based on quintiles of the propensity score distribution, with scores re-estimated weekly throughout recruitment. Participants are recruited if there are <3 unmatched individuals from their group in the same quintile.
Diagnostic interview assessments are reviewed by interviewers and supervised by a licensed clinical psychologist. Participants are informed of their eligibility via phone, with eligible participants scheduled for a laboratory visit ~2–3 weeks later.
Baseline laboratory visit
Participants are instructed to avoid exercise, food and drink (except water), smoking, and use of other tobacco, marijuana or cannabidiol-containing products at least 8 hours before this visit. Medications and vitamins (except diabetes medication, blood thinners, statins and birth control) are avoided for at least 48 hours.
Participants are asked to arrive at the research laboratory by 08:00. They are escorted to a study room for initial measurements and specimen collection; assessments are conducted by a research nurse. Height, weight, waist and hip circumferences, and left arm circumference are measured, and a spot urine sample is collected. An appropriately sized blood pressure cuff is placed on the left arm. After a 5-minute rest, three seated blood pressure measures are taken 1 min apart using a validated device (Omron HEM907XL). Blood is then drawn into serum-separating, citrate and EDTA tubes. The citrate tube is centrifuged immediately and processed to measure EMPs. EDTA tubes are centrifuged within 1 hour of collection at 1500 g at 4°C for 10 min to isolate plasma; aliquots are stored at −80°C for inflammatory marker assays. Serum and whole blood are extracted from serum-separating and EDTA tubes for comprehensive metabolic and lipid panels and haemoglobin A1c, respectively.
Participants are then escorted to a temperature-controlled room to measure brachial artery FMD using a high-resolution, semiautomatic ultrasonography system (UNEXEF38G).79–81 Testing occurs between 08:00 and 10:00 to account for circadian effects on FMD and is conducted according to published guidelines.82 83 Participants lie supine, and a blood pressure cuff is placed around the right forearm. After a 15-minute rest, a baseline measure of brachial artery diameter is obtained. The UNEXEF38G system has a high-resolution linear artery transducer, coupled to computer-assisted analysis software that uses an automated edge detection system for measurement. The cuff is then inflated to 200 mm Hg (or 50 mm Hg above systolic pressure, if >150 mm Hg) for 5 min. Images of the brachial artery are obtained continuously until 2 min after cuff deflation.
After FMD measurement, participants are provided a snack before completing tasks assessing post-traumatic fear and dysphoria. Task order is counterbalanced. Prior to completing the fear conditioning paradigm used to assess post-traumatic fear, participants undergo a heart rate response to deep breathing (HRDB) protocol; both tasks involve psychophysiological measurements. HRDB tests autonomic function, specifically parasympathetic tone.84 Participants lie supine; respiration is measured with a respiration belt and ECG is measured with electrodes placed above the left and right collar bones and on the left lower forearm and recorded with the Biopac MP160 ECG wireless module. ECG and respiration data are collected during a 1-minute resting baseline and 10-second respiratory cycle (5-second inhale, 5-second exhale), repeated six times.84
Post-traumatic fear is assessed using an established fear conditioning protocol with two phases: fear acquisition and extinction.43 85 During fear acquisition, participants complete a four-trial habituation phase in which two coloured shape conditioned stimuli (CS) and a 108 dB, 40-millisecond broadband noise startle probe alone (NA) are presented to familiarise participants. Next, participants undergo a 36-trial conditioning phase, with 3 blocks of 12 trials: 4 reinforced CS (CS+), 4 non-reinforced CS (CS−) and 4 NA trials. CS are presented on a computer monitor for 6 s; the startle probe is delivered binaurally via headphones on every trial after 6 s. During conditioning, only the CS+ is reinforced with an unconditioned stimulus (US) on every trial. The US is a 250-millisecond airblast of 140 psi intensity directed at the larynx, which has consistently produced robust FPS.43 85 On the CS+ trials, the US co-terminates with the CS+ 0.5 s following the startle probe; CS− trials terminate immediately after the startle probe. After a 10-minute break, participants undergo the 72-trial fear extinction phase: 6 blocks of 4 trials of each type (CS+, CS−, NA). During extinction, the CS+ is presented without the US. Intertrial intervals are randomised to be 9–22 s for fear acquisition and extinction.
Psychophysiological fear responses are collected using Biopac MP160 electromyography (EMG) and SC wireless modules; ECG is also recorded. FPS is measured through corrugator and orbicularis EMG. Startle magnitude is assessed as the peak amplitude of EMG contraction 20–200 ms following the startle probe. SC data are collected using electrodes on the hypothenar surface of the non-dominant hand to measure sympathetic arousal. Psychophysiological data are filtered, rectified and smoothed using MindWare software. Several indicators of psychophysiological fear responses are calculated, including: (1) FPS to CS+ during early extinction (fear load),85 (2) FPS to CS+ during late extinction, and (3) FPS to CS− during late fear acquisition. These measures reflect expression of conditioned fear, fear inhibition and fear discrimination.85–87 FPS is calculated by subtracting startle magnitude to the NA from startle magnitude to the CS in each block to account for individual differences in startle magnitude and habituation. Comparable scores for SC response are secondary predictors. Although frequently used to index fear, SC response may be a more non-specific measure of arousal that is not as closely tied to fear neurocircuitry as FPS.87–89 SC response is calculated by subtracting SC prior to stimulus onset from maximum SC during CS presentation.
Post-traumatic dysphoria is assessed with an established and reliable eye-tracking paradigm adapted for dysphoria.90 Attention allocation is measured using a remote high-speed eye-tracker (EyeLink Portable Duo). The task consists of free-viewing 4×4 matrices of NimStim91 happy and sad faces. Trials begin with a fixation cross, shown until a 1000-millisecond fixation is recorded, to verify trials begin with gaze fixated at the matrix’s centre. Matrices are presented for 6000 milliseconds, followed by a 2000-millisecond intertrial interval. Participants view 60 different matrices, presented in 2 blocks of 30 each, with a 60-second break between blocks. Eye-tracking data are used to define fixations as 100+ milliseconds of stable fixation within 1° visual angle. Dwell time for two areas of interest (AOIs)—the eight sad faces and eight happy faces—is calculated for each matrix. Dwell time for each AOI is averaged across the 60 matrices.
Approximately 2 years after the baseline visit, all participants are invited to return for a follow-up; we aim to re-evaluate at least 80 individuals (40+ in each group). At follow-up, participants repeat all procedures from the baseline laboratory visit.
Our primary outcome is brachial artery FMD. As described above, pulsed Doppler velocity signals are obtained at baseline and after cuff deflation using the UNEXEF38G ultrasonography system. FMD is the percent difference in brachial artery diameter, before and after occlusion.
Endothelial cell-derived microparticles
Circulating EMPs expressing CD62E and CD31 (endothelial cell activation and apoptosis, respectively)24 assessed using flow cytometry are secondary outcome measures. EMP sample preparation is completed within 2 hours of blood draw, as previously described.92–95 Citrated blood is centrifuged at 160 g at 4℃ for 10 min to obtain platelet-rich plasma, which is further centrifuged at 1500 g at 4℃ for 6 min to yield platelet-poor plasma. Fifty microlitres of platelet-poor plasma are each incubated in two sets: (1) 4 µL of brilliant violet 421 (BV421)-conjugated monoclonal antibody to CD62E (BD), 4 µL of phycoerythrin (PE)-conjugated monoclonal antibody to CD31 (BD), 4 µL of fluorescein isothiocyanate (FITC)-conjugated monoclonal antibody to CD42b (BD), and (2) 4 µL of PE-conjugated monoclonal antibody to CD31, 4 µL of FITC-conjugated annexin V (BD). EMPs are the number of particles with size <1.5 µm (1) positively labelled by CD62E, (2) positively labelled by CD31 and negatively labelled by CD42b, and (3) positively labelled by CD31 and annexin V. Allophycocyanin (APC)-conjugated monoclonal antibody CD45 (a pan-leucocyte marker; BD) is used to exclude contamination by leucocyte microparticles.93 Negative controls include the appropriate FITC-labelled, PE-labelled, BV421-labelled and APC-labelled isotype-matched IgG. EMPs are quantified as the number of EMPs per microlitre (ThermoFisher Attune NxT Flow Cytometer).
Potential pathway variables
We are exploring autonomic imbalance, inflammation and oxidative stress as potential mechanisms linking PTSD and its dimensions with endothelial dysfunction. Average respiratory sinus arrhythmia amplitude across the cycles of the HRDB task—defined as the difference between the end of expiration and end of inspiration in heart rate—reflects parasympathetic-mediated cardiac control.84 96 Blood-based inflammatory markers are assayed from plasma, including high-sensitivity C reactive protein measured by ELISA (R&D Systems). Interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-α and interferon-gamma are measured in a multiplex assay using a V-PLEX Custom Human Cytokine Proinflammatory Panel on the Meso Scale Discovery electrochemiluminesence platform. Oxidative stress is assessed by measuring urinary F2-isoprostanes using an ELISA (Oxford Biomedical Research).
We will first conduct cross-sectional associations of PTSD and its dimensions with endothelial dysfunction; longitudinal associations will be considered in exploratory analyses.
For cross-sectional analyses, two sample t-tests will compare participants with and without PTSD on (1) FMD and (2) EMPs expressing CD62E and CD31. We will extend these analyses using linear regression models adjusting for covariates (described below). We will consider total PTSD severity score as a continuous predictor. Second, objective measures of post-traumatic fear (eg, fear load based on FPS) will be the exposures in cross-sectional linear regression analyses of FMD and EMP outcomes. Additionally, we will explore objective measures of post-traumatic dysphoria as predictors of endothelial dysfunction. The approach for these analyses will mirror that for post-traumatic fear, with exposures operationalised as total dwell times for the sad and happy AOIs.
For longitudinal analyses, we will first examine how measures of PTSD and its dimensions at baseline predict change in FMD using linear regression, and then examine how changes in PTSD and its dimensions over follow-up predict change in FMD using linear regression. Analyses will consider EMPs as secondary outcomes. For longitudinal analyses, FMD or EMPs at follow-up will be the outcome; FMD or EMPs at baseline will be a covariate.
To examine if autonomic imbalance, inflammation and oxidative stress explain associations of PTSD and its dimensions with endothelial dysfunction in cross-sectional and/or longitudinal analyses, we will estimate total and direct effects of measures of PTSD and its dimensions on endothelial dysfunction and test for significant indirect effects using bootstrapping methods.97
For all analyses, we will examine a series of adjusted models. The base adjusted model will include age, gender, race and ethnicity; subsequent models will sequentially adjust for: (1) other sociodemographics (eg, education, marital status); (2) CVD medical risk factors (eg, diabetes, hypertension); (3) medications (eg, medication for hypertension, hyperlipidaemia); and (4) anthropometrics and health behaviours (eg, body mass index, smoking). Even though post-traumatic fear has been found to be distinct from the core symptoms of depression,42 98 we will also consider depression as a potential confounder given high comorbidity of PTSD and depression.2 Data on depression diagnoses and symptoms will be examined as covariates, and we will explore how comorbidity of PTSD and other psychopathology (eg, depression) relates to endothelial dysfunction. To avoid overfitting in adjusted models, we will fit group lasso regression, which performs variable selection and regularisation of regression coefficients, to identify important predictors of endothelial dysfunction and improve model interpretability.99
Sample size estimation and power
Analyses are powered to our primary outcome, FMD, and based on the smallest effect size from prior research to be conservative in our calculations. We estimated our effect size based on Cohen’s d=0.48 for the difference in per cent change in FMD in patients with versus without PTSD.28 Power analysis for two sample t-tests was conducted to determine a sufficient sample size using α=0.05, power=0.80, a medium effect size (Cohen’s d=0.48), two tails, and equal allocations of participants to the PTSD and trauma control groups. Based on these assumptions, the desired sample size was 70 participants per group. We conservatively selected 80 participants per group.
Given our hypothesis that psychophysiological fear is the key PTSD dimension that will relate to endothelial dysfunction, we considered power for this analysis based on our primary exposure for this aim: FPS. We assumed an SD of 70 for FPS scores85 and an SD of 3.5% for FMD.28 With N=160 and a two-sided significance level of 0.05, we have 80% power to detect a change of 0.011% in FMD for each unit of FPS score increase.100 This is a small effect size,28 so our sample is large enough to model psychophysiological fear and FMD in adjusted models.
Ethics and dissemination
This study is conducted in compliance with the UCLA Institutional Review Board and Helsinki Declaration. Participants sign informed consent and Health Insurance Portability and Accountability Act Authorization for Research forms at enrolment. Research personnel review the study in detail and answer questions. Individuals are informed that participation is optional and that they may withdraw at any time. After individuals are fully informed about study procedures, participants who elect to proceed with the study sign the consent document, as do research personnel. The findings of this study will be disseminated online (ClinicalTrials.gov, Open Science Framework), presented at conferences and published in peer-reviewed journals.
Patient and public involvement
Patients and the public were not involved in the design or conduct of the study. We plan to share findings with the public through dissemination to community partners.
This is the first study to comprehensively investigate the ways in which PTSD and dimensions of post-traumatic stress relate to endothelial dysfunction, one of the earliest modifiable precursors to CVD. To distil pathways by which post-traumatic stress may lead to CVD risk, we focus on psychophysiological fear—a key dimension of PTSD—although we consider objective measures of dysphoria, a more non-specific dimension. This study incorporates state-of-the-art measures of endothelial dysfunction by investigating brachial artery FMD and EMPs. No investigation of trauma-exposed individuals has considered functional and cellular measures of endothelial dysfunction as we do here. Furthermore, unlike prior research with predominantly white male samples,27 28 this study will include men and women of diverse racial/ethnic backgrounds who have been exposed to a range of traumas, increasing generalisability of findings.
Despite these strengths, there are limitations. Assessments are conducted in the laboratory, which offers a controlled environment that enhances internal validity but limits generalisability to real-world settings. Additionally, although we use state-of-the-art measures of endothelial dysfunction, neither metric indicates endothelial function reactivity to trauma-related cues. Further research using provocation measures or assessing cardiovascular reactivity in naturalistic settings is needed to address this issue.
PTSD predicts incident CVD, but the field needs intervention targets and intermediary mechanisms to determine if PTSD interventions can offset CVD risk. This study will test whether endothelial dysfunction could be an early subclinical, modifiable mechanism by which PTSD increases CVD risk, and whether post-traumatic fear or another dimension could be the target to offset that risk in vulnerable, trauma-exposed individuals in future intervention studies.
Contributors JAS, DS, YN, AL, OAA, RE, TH and KW-T contributed significantly to the planning, conception, design and successful funding of this study. SC, KR, JLT, JAS and KW-T are contributing significantly to the acquisition of data. SC, KR and JAS drafted the initial version of this manuscript. AKM, DS, YN, AL, OAA, RE, TH and JAS will be involved in the analyses and interpretation of the data. All authors revised the draft critically for important intellectual content and gave final approval for this version of the manuscript to be submitted for publication.
Funding This study is supported by the National Heart, Lung, and Blood Institute (NHLBI) (grant number: R01HL139614).
Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Author note SC and KR contributed equally to this work.
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