A PTSD Mouse Model Links Stress with Acute Heart Injury

PTSD Mouse Model Stress Acute Heart Injury
PTSD – Stress – Heart Injury

In the February 2014 issue of the Proceedings of the National Academy of Sciences of the USA (PNAS) Ji-Hoon Choa and colleagues from the Institute for Systems Biology, Seattle, WA, USA, used an adapted aggressor-exposed social stress mouse model for PTSD to demonstrate genetically associated stress-induced tissue injuries on peripheral organs, including the heart.

Posttraumatic stress disorder (PTSD) is perhaps the most common psychological disorder as ~7% of the US population suffers, at any given time, from some form of this condition. In general, PTSD is a psychiatric disorder that occurs in 7–8 % of civilians and as many as 20% of military veterans.

Individuals with PTSD have dysfunctional hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system (SNS) – the two branches of the peripheral stress system – with elevated norepinephrine (NE, noradrenaline) levels in the cerebrospinal fluid and higher NE/cortisol urinary ratios. Importantly, these individuals also have a higher risk of cardiovascular conditions such as hypertension and stroke, with an increased basal heart rate and blood pressure, and elevated blood cholesterol levels.

Jacob Mendes Da CostaJacob Mendes Da Costa. Source: National Library of Medicine. Credit: Wikimedia Commons.

The first association between ‘PTSD’ and heart conditions was perhaps made by Jacob Mendes Da Costa in 1871 when he described that serious cardiac conditions (cardiomyopathy, heart failure, heart pain, etc.) were probably caused by the extended stress exposures in Civil War soldiers (Da Costa’s syndrome, also known as ‘soldier’s heart’ or ‘irritable heart’ syndrome).

More recently the stress-induced cardiomyopathy, or the ‘Takotsubo’ cardiomyopathy, has been linked to stress-induced inflammation, and particularly catecholamine-induced inflammation that may drive acute symptoms and transiently altered heart functions.

Now, the authors of the PNAS study found that the acute heart injury induced by this experimental PTSD stress model is associated with underlying biological injury processes and alterations of key molecular processes, including an inflammatory response, extracellular matrix remodeling, epithelial-to-mesenchymal transitions (EMTs) and cell proliferation.

Most of the changes in the heart transcriptome occurred after 3 days, but the authors could clearly document some stress-induced effects, such as the up-regulation of a battery of inflammation-related genes, after as little as 1 day of exposure to stress. Of note, the investigators report a gradual increase in the adenosine deaminase transcript level, which may indicate a compensatory process in heart tissue to reduce the adenosine level after the tissue is in the wound-healing stage.

In addition, the reported differing responses to stress leading to acute heart injury in different inbred strains of mice may imply that in humans the inter-individual variations of susceptibility to stress/PTSD effects may have a genetic as well as an environmental component.

According to the authors the finding of acute heart injury in this animal model suggests common stress-induced heart impairment. These results may also suggest that further studies investigating the effects of acute/chronic stress or PTSD on heart tissue damage are warranted.

Source: Proc Natl Acad Sci U S A, 2014, 111:3188-93. doi: 10.1073/pnas.1400113111. Epub 2014 Feb 10.
Read more: pnas.org


In a 2017 narrative review, Donald Edmondson, PhD1 and Roland von Känel, MD summarized some recent evidence for an association of PTSD with incident cardiovascular disease (CVD) risk. The current understanding of the link between PTSD and CVD is that PTSD is likely an independent risk factor for acute cardiac events including acute coronary syndromes (i.e., myocardial infarction or unstable angina) and possibly stroke.

An important new development has been the investigation of the association of PTSD with new-onset venous thromboembolism (i.e., deep vein thrombosis and pulmonary embolism), as many of the risk factors for CVD events are also contributors to venous thromboembolism risk.

Sympathetic nervous system activity is exaggerated, thus, patients with PTSD exhibit higher catecholamine levels and higher heart rate relative to those without PTSD, particularly after exposure to reminders of their index traumatic event. High heart rate is a major risk factor for recurrent cardiac events and mortality in CVD patients.

Chronic increases in cardiovascular demand degrade the capacity of the cardiovascular system to support that increased demand. This appears to be linked to CVD risk through the development of a systemic proinflammatory state, and thus more rapid progression of atherosclerosis, endothelial dysfunction, hypertension, and more pronounced coronary ischemia under stress.

One of the earliest markers of degraded capacity to support increased cardiovascular demand is endothelial dysfunction. Also, PTSD symptom severity has been associated with a proinflammatory state, and as per a meta-analysis, significantly higher levels of IL-1β, IL-6, and interferon γ were found in patients with PTSD relative to controls.

Given the autonomic, HPA axis, endothelial, and inflammatory correlates of PTSD, it is not surprising that PTSD has been associated with increased clinic and ambulatory blood pressure. Most of the research on PTSD and risk for incident hypertension has been conducted in US veterans.

A hypercoagulable state along with hyperactive platelets might facilitate acute atherothrombotic CVD events in conjunction with endothelial dysfunction and inflammatory processes in PTSD. Hypercoagulability may be particularly important in CVD patients.

A 2020 study demonstrates that rats exposed to the predator-based stress model of PTSD develop multifocal cardiac lesions characterized by myofiber necrosis, fibrosis, and infiltration by mononucleated immune cells. This was accompanied by changes in gene expression associated with endothelial cell migration, mesenchymal development, and extracellular matrix organization. In addition, changes in the expression of markers for endothelial to mesenchymal transition were observed at both the mRNA and protein levels. These data provide evidence of cardiac stress and tissue remodeling in rats exposed to predator stress.

Thus, overall, predator stress promotes myocardial necrosis, collagen deposition, infiltration of immune cells and reprogramming of myocardial gene expression. These data are consistent with previous work demonstrating that people who develop PTSD and other forms of chronic stress are at increased risk of developing cardiac disorders such as myocardial infarction and arrhythmias.