Sex-dependent effects of chronic psychosocial stress on myocardial sensitivity to ischemic injury

Abstract

Individuals with post-traumatic stress disorder (PTSD) experience many debilitating symptoms, including intrusive memories, persistent anxiety and avoidance of trauma-related cues. PTSD also results in numerous physiological complications, including increased risk for cardiovascular disease (CVD). However, characterization of PTSD-induced cardiovascular alterations is lacking, especially in preclinical models of the disorder. Thus, we examined the impact of a psychosocial predator-based animal model of PTSD on myocardial sensitivity to ischemic injury. Male and female Sprague-Dawley rats were exposed to psychosocial stress or control conditions for 31 days. Stressed rats were given two cat exposures, separated by a period of 10 days, and were subjected to daily social instability throughout the paradigm. Control rats were handled daily for the duration of the experiment. Rats were tested on the elevated plus maze (EPM) on day 32, and hearts were isolated on day 33 and subjected to 20 min ischemia and 2 h reperfusion on a Langendorff isolated heart system. Stressed male and female rats gained less body weight relative to controls, but only stressed males exhibited increased anxiety on the EPM. Male, but not female, rats exposed to psychosocial stress exhibited significantly larger infarcts and attenuated post-ischemic recovery of contractile function compared to controls. Our data demonstrate that predator stress combined with daily social instability sex-dependently increases myocardial sensitivity to ischemic injury. Thus, this manipulation may be useful for studying potential mechanisms underlying cardiovascular alterations in PTSD, as well as sex differences in the cardiovascular stress response.

The heartbreak of depression: ‘Psycho-cardiac’ coupling in myocardial infarction

“…subjecting animals to physical restraint, social isolation, predation stress, forced swimming, environmental instability, and randomized series of such stressors), which exhibit symptoms of depression that may include anhedonia and decreases in sexual drive, aggression, investigative behavior and locomotion, together with circadian disruption, disordered sleep and weight loss [38,39] (models discussed below in section 4). These studies identify both ultrastructural disruption in otherwise healthy hearts [40,41] and substantial changes in myocardial injury responses [40,[42][43][44][45][46][47]. However, they have not yet developed a mechanistic understanding of these cardiac outcomes.…”

“…Ravingerova et al found chronic stress also increases contractile dysfunction and risk of post-ischemic arrhythmias in normotensive rats, though stress somewhat paradoxically improved these parameters in hypertensive animals [45]. While emulating posttraumatic stress disorder (PTSD), a more recent study in a psychosocial predator-based animal model reports increases in contractile dysfunction and myocardial death following ischemia, though specifically in males and not females [46]. Delving into mechanistic elements, Rakhshan et al found that chronic physical or psychological stress worsened myocardial damage during infarction, and that this effect was eliminated by chemical sympathectomy (without influencing corticosterone levels) [47].…”

“…These intriguing observations of acute protection via simple environmental enrichment warrant further investigation, highlighting the importance of psychological state in dictating myocardial phenotype and also raising questions regarding behavioral status in 'control' caged rodents. Finally, it is relevant to note there is evidence that the impacts of differing types of stress may be sex-dependent, with a model of PTSD selectively exaggerating post-ischemic myocardial damage and dysfunction in males only [46], while in contrast other stress (eg. crowding, sleep deprivation) worsens ischemic outcomes in females and not males [51,56].…”

“…Chronic stress also increases macrophage infiltration and growth and vulnerability of atherosclerotic plaques, in association with exaggerated infarct occurrence and injury [210]. [212][213][214][215][216], sex- [46,51,217,218] and agedependent [219][220][221][222] outcomes and responses to anti-depressants.…”

Predator-based psychosocial stress animal model of PTSD: Preclinical assessment of traumatic stress at cognitive, hormonal, pharmacological, cardiovascular and epigenetic levels of analysis

“…Because previous work with our model of PTSD revealed long-term adverse effects on cardiovascular reactivity (e.g., hypertension), as well as increased levels of inflammation, we explored whether the model would exacerbate myocardial damage following experimentallyinduced ischemia (Rorabaugh et al, 2015). After the 31-day stress paradigm, rats were anesthetized, and their hearts were removed and placed in a Langendorff isolated heart system.…”