The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop on “The Cardiovascular Consequences of Post-Traumatic Stress Disorder,” in Bethesda, Maryland from November 13-14, 2018. The workshop gathered leading experts in basic, translational, clinical, and population research in cardiovascular disease (CVD), post-traumatic stress disorder (PTSD), and neuroscience, as well as representatives of multiple federal and non-federal agencies and academic institutions. Their charge was to identify the highest priority research gaps and make recommendations for future research strategies to address these gaps, with a specific focus on the following objectives:
The workshop is responsive to NHLBI Strategic Vision Objectives 1-5 and 7.
Experiencing traumatic events such as violent personal assaults, natural or human-made disasters, serious accidents, or military combat can lead to the development of PTSD, a psychiatric condition characterized by a persistent maladaptive reaction to exposure to severe psychological trauma. PTSD is associated with an increased risk of CVD events, including coronary heart disease, heart failure, and stroke. It is also associated with CVD risk factors such as hypertension and diabetes, and with accelerated progression of CVD, particularly heart failure. Evidence for this increased risk includes prospective data showing an association between a PTSD diagnosis or symptoms and CVD events, including coronary artery disease, stroke, and heart failure in cohorts of United States veterans and in a large longitudinal study of U.S. nurses.
Despite these observations, prospective data from well-designed studies with measurement of potential complex confounding factors remain limited. The biological and behavioral mechanisms linking PTSD with CVD risk are not well defined. Mechanisms of stress regulation that are thought to be altered in PTSD and that also may affect the cardiovascular system include the hypothalamic-pituitary-adrenal axis; the thyroid axis; immune regulation; peptide regulation, such as pituitary adenylate cyclase-activating polypeptide; and the renin-angiotensin/vasopressin system; and adrenergic/autonomic nervous system regulation. In addition, possible mechanisms of shared risk across CVD and PTSD include shared genetic and epigenetic pathways, trauma-related factors, and metabolic risk factors. Confounding factors resulting from traumatic events, in addition to PTSD, that can affect CVD risk in those exposed to trauma with PTSD include changes in health risk behaviors (e.g., disrupted sleep patterns, maladaptive dietary changes, tobacco use, substance abuse, physical inactivity, and non-compliance with medical therapy) and other associated comorbidities of PTSD (e.g., depression). There is also a well-described association of PTSD that may occur after a life-threatening CVD event, such as cardiac arrest, or repeated shocks by an internal cardiac defibrillator, highlighting associations of CVD with risk for PTSD.
Participants at the workshop identified numerous major clinical and research gaps and provided recommendations for future scientific directions to illuminate the mechanisms of the relationship of PTSD with CVD, CVD subtypes, and CVD risk factors. A top priority is to establish stronger evidence for causal relationships and genetic/environmental/behavioral modifiers of the relationship of PTSD with CVD/CVD risk factors. Numerous population-based studies and biobanks are now available that may allow more rigorous clinical, translational, and population studies, including studies that incorporate omics (including genomics, proteomics, and metabolomics), critical biomarkers, and high-resolution imaging of the brain and heart. The most valuable of these for study of PTSD is the U.S. Department of Veterans Affairs (VA) Million Veterans Program (MVP). Other population-based studies and biobanks may require de novo measurements to identify the presence of PTSD.
Questions remain unanswered regarding the basic mechanisms that link PTSD and CVD, including the role of inflammation and immune dysfunction, oxidative stress and mitochondrial abnormalities, autonomic nervous system dysregulation, and endothelial dysfunction. The workshop participants identified the following critical research gaps in PTSD and CVD prevention: 1) the need to create a research network that would facilitate collaboration among investigators and integration of data from both the cardiovascular and psychiatric fields to infer causal relationships from clinical and population studies; 2) the need to identify specific biochemical mechanisms through basic research or human physiological/molecular studies which can inform the discovery of robust preclinical markers of disease; 3) the need to have more refined and evidence-based screening techniques and approaches; and 4) the need to identify therapeutic targets and approaches through translational research ultimately leading to clinical trials.
THE FOLLOWING SCIENTIFIC AREA Gaps and Priorities WERE IDENTIFIED:
Priority: Database/Epidemiological Studies
1. Gap: Lack of prospective, longitudinal measures of both PTSD and CVD (and CVD risk factors) in existing community-based epidemiology cohorts
2. Gap: Lack of rigorous measures of trauma exposure and PTSD symptoms in most existing electronic health record (EHR) databases that have data on CVD and CVD risk factors
3. Gap: Lack of data on racial, ethnic, and sex differences in PTSD-CVD risk association
Priority: Experimental/Interventional Studies
1. Gap: Lack of comprehensive, robust, longitudinal approaches, including multivariable analysis and systems biology approaches, to study biological mechanisms linking PTSD and CVD
2. Gap: Lack of comprehensive evaluation of multiple health behaviors as mediators/moderators of PTSD-CVD association
3. Gap: Lack of interventional experimental studies to enhance the evidence for or against causal mechanism(s) in the PTSD-CVD association
4. Gap: Lack of clinical studies assessing how intervening on PTSD risk or symptoms impacts CVD risk factors or CVD outcomes
Priority: Genetic and Genomic Studies
1. Gap: Lack of large-scale datasets with deep genetic data and both PTSD and CVD (and CVD risk factor) measures for genetic and genomics studies
2. Gap: Lack of population cohort studies and biobanks to harness genetics and genomics to understand shared risks of PTSD and CVD, to identify components and subtypes of PTSD with increased CVD risk, to identify possible gene targets for interventions to reduce CVD risk in PTSD, and to enhance causal inference
3. Gap: Lack of polygenic risk scores from genome-wide association studies (GWAS) of PTSD and CVD to inform potential causal PTSD-CVD associations and identify potential therapeutic targets
Priorities: Atherosclerosis, Circulating Factors, Brain-Heart Communications
1. Gap: Lack of studies of basic mechanisms, including immune function, autonomic dysregulation and neurohormonal factors, linking PTSD and CVD in human studies and animal models
2. Gap: Lack of human tissues (e.g., brain and heart) to study basic mechanisms of CVD and PTSD linkage
3. Gap: Lack of clear characterization of the specific abnormalities of brain circuitry, including brain signatures/function/activity (e.g., function in the amygdala) in PTSD that may be contributing to CVD
4. Gap: Identify the role of bioenergetics (e.g., oxidative stress) and markers of mitochondrial health in PTSD and subsequent studies of association with CVD
5. Gap: Identify whether genes associated with CVD modulate PTSD-associated mechanisms
A white paper outlining the recommendations that arose from the workshop is in preparation.
Lisa Schwartz Longacre, PhD, Division of Cardiovascular Sciences (DCVS)/Heart Failure and Arrhythmia Branch (HFAB)
Rebecca Campo, PhD, DCVS/Clinical Applications and Prevention Branch (CAPB)
Narasimhan Danthi, PhD, DCVS/Advanced Technologies and Surgery Branch
George Sopko, MD, DCVS/HFAB
Catherine Stoney, PhD, FABMR, DCVS/CAPB
Michael Twery, PhD, Division of Lung Diseases, National Center on Sleep Disorders
Terri Gleason, PhD, US Department of Veterans Affairs
Mario Rinaudo, MD, US Department of Veterans Affairs
Ian M. Kronish, MD, MPH, American Heart Association
Andrew Midzak, PhD, US Army Medical Research and Materiel Command
Center for Scientific Review
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Cancer Institute
National Center for Advancing Translational Sciences
National Center for Complementary and Integrative Health
National Institute of Allergy and Infectious Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Drug Abuse
National Institute of Mental Health
National Institute of Nursing Research