Abstract
Cardiovascular disease (CVD) is the largest cause of mortality worldwide, and stress is a significant contributor to the development of CVD. The relationship between acute and chronic stress and CVD is well evidenced. Acute stress can lead to arrhythmias and ischemic injury. However, recent evidence in rodent models suggests that acute stress can decrease sensitivity to myocardial ischemia–reperfusion injury (IRI). Conversely, chronic stress is arrhythmogenic and increases sensitivity to myocardial IRI. Few studies have examined the impact of validated animal models of stress-related psychological disorders on the ischemic heart. This review examines the work that has been completed using rat models to study the effects of stress on myocardial sensitivity to ischemic injury. Utilization of animal models of stress-related psychological disorders is critical in the prevention and treatment of cardiovascular disorders in patients experiencing stress-related psychiatric conditions.
Introduction
The goal of this review is to analyze recent literature utilizing rodent models to examine the impact of psychological stress on sensitivity to myocardial ischemia–reperfusion injury (IRI) in the context of the well-established relationship between stress, myocardial ischemic injury, and cardiovascular disease (CVD). Stress is a general adaptive response provoked by stimuli that disrupt homeostasis (1, 2). The stress response activates systems responsible for mobilizing the energy and resources necessary to overcome this homeostatic disturbance. The main systems activated include the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic adrenomedullary (SAM) system (3, 4). Stress results in the release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus, which then causes the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH acts on the adrenal cortex to synthesize and secrete the glucocorticoid (GC) hormone cortisol (in humans) or corticosterone (in rodents) (3, 5). The hypothalamus also activates the adrenal medulla via the sympathetic nervous system (SNS), which results in the release of the catecholamines epinephrine and norepinephrine. ACTH, CRH, and GCs provide the negative feedback necessary to dampen the stress response and return the body to homeostasis (4, 6). Cessation of the stress response is important to prevent damage associated with a prolonged stress response (3, 4, 7). Acute stress generally results in an adaptive response to homeostatic changes; the stress response becomes harmful if it persists chronically (8–11). Thus, stress research can be roughly divided into research examining the effects of acute or chronic stress (3, 4, 7, 9–11).
Physical or psychological stressors can result in the stress response. Physical stressors disrupt the internal or external environment of an organism and include stimuli such as anoxia, heat, cold, or physical strain (exercise or injury). Psychological stressors are stimuli that affect emotion and result in fear, anxiety, or frustration (8–11). As previously discussed, anything disrupting homeostasis can be a stressor; however, this review focuses on stressors with a psychological component.
Chronic stress can have damaging effects on the whole organism (4). Stress precipitates psychiatric disease, such as depression and post-traumatic stress disorder (PTSD), and worsens physical health outcomes, such as CVD (12, 13). Furthermore, patients with psychiatric disorders have a higher incidence of CVD and cardiovascular risk factors, such as atherosclerosis, hypertension, and myocardial infarction (MI) (14–16). Patients with psychiatric disorders experience worse outcomes in response to cardiovascular disorders (e.g., higher mortality). It is suggested that appropriate monitoring for psychiatric disorders could improve outcomes in patients with ischemic heart disease (8, 14, 17–21). Thus, research directed at minimizing the negative impact of stress is important (19, 21–25).
Stress and Cardiovascular Disease
Cardiovascular disease is the leading cause of mortality worldwide (26, 27), and stress is a well-established contributor to the development of CVD (3, 8, 20). Stress is relevant at all stages of CVD; stress can increase exposure to risk factors for CVD (e.g., smoking), the long-term development of atherosclerosis, and the triggering of cardiac events in people with CVD (28).
The most common form of CVD is ischemic heart disease (also known as coronary artery disease), which includes disease states such as angina, MI, and sudden cardiac death (SCD) (29, 30). MI occurs when blood flow to a region of the heart stops. The heart is an electromechanical pump; SCD most commonly occurs in response to ventricular fibrillation, a disturbance in electrical activity, as a result of acute coronary ischemia (31, 32). MI and SCD can lead to cardiac arrest and death. Stress may acutely trigger MI or SCD or worsen underling CVD leading to one of these events (3). Thus, stress is closely related to ischemic heart disease. Research investigating the relationship between stress and the cardiovascular system is critical to improve patient outcomes in CVD (20, 25, 28).
Myocardial Ischemia–Reperfusion Injury
Myocardial IRI refers to the damage created by the stoppage of and the subsequent restoration of blood flow to the heart. Without blood flow, an imbalance between oxygen supply and demand is created which results directly in irreversible damage to cardiac tissue, eventually resulting in apoptosis or necrosis; this oxygen imbalance is referred to as ischemia. The duration of ischemia and amount of tissue exposed to ischemia are well established as the primary determinants of infarct size (IS), or the amount of non-viable tissue following ischemia. The mechanisms by which damage and protection occur in response to myocardial IRI has been described in detail previously (33–39). Thus, myocardial IRI is the primary mechanism by which cardiac tissue is damaged in MI, SCD, cardiac bypass surgery, and organ transplantation (40). Acute and chronic stress has an impact on myocardial IRI (3, 41, 42). Because myocardial IRI plays a major role in the morbidity and mortality associated with ischemic heart disease and MI, direct study of this pathology is desirable (35, 43–46). To better elucidate the mechanisms underlying CVD and ischemic injury, researchers have utilized animal models.
The Utility of Animal Models in Stress Biology and Cardiovascular Disease
Animal models are used extensively to study the relationship between stress and CVD. Animal models are especially important in studying stress biology, as they allow researchers to standardize the conditions of stress. Furthermore, a high level of experimental control and the potential to study causal neurobiological and behavioral mechanisms (with easier access to tissue samples and physiological manipulation) makes animal models advantageous for studying cardiovascular function and stress (22, 47, 48). By using validated methodology with translational relevance to human patients, researchers can use animal models effectively to examine underlying mechanisms and potential treatment options in CVD and stress (22, 49).
The Langendorff Isolated Heart – An Experimental Model of Ischemic Injury
Animal models have been developed to experimentally induce and study acute ischemia both in vivo (50, 51) and ex vivo (44, 52, 53). The Langendorff isolated heart preparation is one of the most extensively used animal models for the study of heart physiology and ischemia (53). In this model, crystalloid perfusates (or blood) is delivered through a cannula inserted in the ascending aorta. Retrograde flow closes the leaflets in the aortic valve, leading to perfusion of the coronary vasculature (52, 53). This model is commonly used to study myocardial IRI. This is accomplished by occlusion of a coronary artery (typically the left anterior descending artery), leading to regional ischemia, or by turning off flow, leading to global ischemia. This model allows the generation of data including IS, the recovery of contractile function, and electrical activity in response to induced ischemia. In regional ischemia, researchers use the IS relative to the area at risk (AAR), or the area normally perfused by the clamped artery, whereas global ischemia allows measurement of the total amount of non-viable tissue [for a complete methodological review of the Langendorff isolated heart, see Ref. (52)].
Notably, the Langendorff isolated heart system studies ischemic injury in the absence of normal humoral or neuronal stimulation, potentially limiting the translation of experimental findings to the clinical setting (52, 53). Furthermore, this model has additional disadvantages, including a high coronary flow rate, limited supply of high-energy phosphate, a reduced oxygen requirement, and a degree of technical skill required to perform successfully (53–55). These disadvantages have led to the development of alternative methods to study cardiovascular injury; other potentially more clinically relevant methods include altering the Langendorff procedure (54) or using in vivo models of cardiovascular injury (56). Despite its disadvantages, the Langendorff isolated heart system has proven invaluable to the study of myocardial IRI (52, 53). This model has been used effectively to identify potential strategies and pharmacological agents to decrease the amount of damage caused to the heart following MI (43, 53).
The Langendorff Isolated Heart Preparation in Rats
The Langendorff heart preparation is appropriate in mammalian species. Although this preparation has been used rarely in large animals or man (57–61), the most frequently used isolated heart model is that of the rat. The rat model allows for relatively low costs, easy handling, and uncomplicated equipment (53). Furthermore, the consistency of limited collateral circulation allows the study of regional ischemia in the rat. This provides an advantage over models with significant collateralization such as dog (62), guinea-pig (62, 63), and hamster models (63). Furthermore, the rat’s consistent coronary structure makes it a better model than, for example, rabbits, whose coronary structure varies significantly between animals (64). However, it is important to recognize that the rat suffers distinct disadvantages in cardiovascular study because of its short action potential duration, which lacks a plateau phase. This makes this animal a poor choice for study of arrhythmogenesis and antiarrhythmic drugs (60, 65–68). Similarly, dogs have been shown to have elevated levels of troponin and creatine kinase, markers of cardiac damage, in response to cardiac injury (69). However, rats have only shown elevations in troponin, making them relatively poor candidates to study drug-induced injury using these markers (69, 70). Thus, one must remain mindful of the potential clinical relevance of studies in the context of the species being utilized (52).
Both myocardial ischemic injury and cardiovascular responses to stress have been described in detail in both human patients and animal models; however, only several recent studies have focused directly on the sensitivity to myocardial ischemic injury in response following acute or chronic psychological stress exposure.
Acute Stress and Cardiovascular Disease
The association between acute stress and cardiac rhythm, acute MI, SCD, and stress cardiomyopathy has been supported by epidemiological studies (71–75). Cardiac rhythm changes in response to acute stress has been evidenced by a marked increase in tachyarrhythmia among patients with implanted cardioverter defibrillators in the New York area of the USA during the attacks on the World Trade Center on September 11, 2001 (71). An association between intense emotional stress or anger and the triggering of acute cardiac events, such as acute MI or SCD, has been demonstrated by multiple studies demonstrating a significant number of patients experiencing an emotional episode roughly 2 h before cardiac arrest (72–75). This increased incidence of MI has been evidenced in individual patients following a significant acute stressor, such as the loss of a loved one. Moreover, acute cardiac event incidence is increased in geographical areas where a major trauma, such as an earthquake, serves as an acute stressor (8, 20, 76). SCD and MIs are rare in patients with no underlying coronary heart disease, whereas stress cardiomyopathy can occur with no underlying disorder (77–79).
Acute Stress and Myocardial Ischemic Injury
The association between intense emotional stress and ischemic heart disease, specifically the incidence of SCD, has been researched for over 50 years (80, 81). Acute psychological stress in human patients leads to ischemia, stress cardiomyopathy, MI, and SCD (8). Stress cardiomyopathy is induced by intense stress that results in heart weakness without underlying pathology. Thus, stress cardiomyopathy is a recently identified disease state mirroring MI with symptoms, such as chest pain and ECG abnormalities, but without concomitant coronary spasm or ischemia-induced enzymatic release (82, 83). Mental stress elicits regional ischemic damage due to epicardial or microvascular constriction, as evidenced by changes in regional perfusion. Interestingly, this ischemia is not associated with the angina and ECG changes that are associated with exercise-induced stress (84–89). This transient myocardial ischemia and coronary artery constriction have been shown to occur in patients with advanced coronary artery disease in response to mental stress (89–91). Furthermore, mental stress has been shown to lead to ECG alternans, a predictor of ventricular arrhythmias and SCD (92–94).
Acute mental stress has been shown to alter the action potential duration of cardiac tissue in humans. Adrenergic stimulation with isoprenaline and adrenaline increases the steepness of the slope of action potential duration restitution; this suggests that adrenergic stimulation can lead to electrical instability, which could lead to ventricular fibrillation or arrhythmias (95). In an elegant study, Child et al. showed that a mental challenge was able to elicit this effect on action potential duration independent of the respiration or heart rate changes that occur in response to mental stress (96). Ventricular fibrillation has been shown to occur in response to both regional myocardial ischemia and electrical instability. Ventricular fibrillation leads to global cardiac ischemia, which can lead to cardiac death (97, 98). The ability of mental stress to cause cardiac ischemia and electrical instability in the heart is supported by epidemiological studies. The underlying risk factors inherent in clinical study complicate cardiovascular research. As previously discussed, the standardization of stress conditions makes animal models advantageous for investigating the underlying pathology of disease, including CVD.
Experimental Acute Stress and Cardiovascular Disease
Experimental work using animal models supports the effects of acute psychological stress on the cardiovascular system seen in human patients. Psychological stress has been shown to reduce the ventricular fibrillation threshold in dog (42, 99–103) and porcine models (104). Verrier and colleagues have demonstrated the ability of acute stress to precipitate ventricular arrhythmias in dogs exposed to anger and fear in both healthy hearts and hearts exposed to coronary artery occlusion (99–103, 105–108). Acute stress was able to precipitate ventricular fibrillation and cardiac arrest; albeit, these studies did not utilize dogs exposed to a single acute stressor but rather an acute stress session following aversive conditioning (99–101, 103). These researchers found that behaviorally induced changes in vulnerability to fibrillation are mediated by the direct effects of catecholamines on beta receptors (109, 110). Further supporting the centrally mediated nature of cardiac arrhythmias generated by acute stress, Skinner and Reed were able to prevent an increase in ventricular fibrillation by cryogenic blockage of the forebrain, posterior hypothalamus, or fields of Forel (104). Thus, acute psychological stress has the ability to generate and exacerbate ischemia and ventricular arrhythmia.
Stress-limiting endogenous systems have been identified with the ability to abolish or reduce cardiac arrhythmias in response to sympathetic stimulation, acute stress, or ischemic injury (4, 7). The endogenous hormones utilized by these systems with protective effects on the cardiovascular system include GABA (111, 112), opioids (113), or vagal stimulation with cholinergic agonists (114, 115). Furthermore, it has been suggested that electrical instability does not necessarily disturb cardiac contractility (4, 116). Supporting the role of stress-limiting systems in cardiovascular injury, recent work in rodents demonstrates that acute stress may decrease damage in response to induced regional ischemia, possibly as a compensatory mechanism.
Experimental Acute Stress and Myocardial Ischemic Injury
Recent rodent studies looking at the effect of acute psychological stress on the impact of myocardial ischemic injury have found acute stress to be cardioprotective and reduce IS [see Table 1 (45, 117)]. The identified relevant studies utilized cold-restraint stress (117) and forced swim stress (45) before using the Langendorff method to induce regional ischemia. Acute swim stress and acute restraint stress are validated psychological stressors that have been used in combination with other stressors to model PTSD and depression (118–121). These stressors, individually or in combination, have resulted in anxiety-like and fear-related behavior in rodents as assessed by tests such as the elevated plus maze (EPM) and contextual fear conditioning (CF) (119, 122, 123). The decreased sensitivity to myocardial IRI provided by acute psychological stress is supported by similar findings in studies utilizing acute physiologic stressors, such as exercise or hyperthermia (124–128). The existence of endogenous signaling pathways that protect the heart from ischemic injury is well evidenced (46, 129–131).
Table 1
| Subjects | Stress protocol | Reperfusion injury (RI) protocol | Primary finding | Reference |
|---|---|---|---|---|
| Acute psychological stress | ||||
| Adult male Wistar rats | Forced swim for 10 min | 30 min ischemia | Decreased infarct size (IS)/area at risk (AAR)% | Moghimian et al. (45) |
| RI 10 min after | 60 min reperfusion | |||
| Adult male Sprague-Dawley rats | Individual immobilization, placed in a cold room for 3 h at 4 ± 0.3°C | 30 min ischemia | Decreased IS/AAR% | Wu et al. (117) |
| RI immediately after | 120 min reperfusion | |||
| Chronic psychological stress | ||||
| Adult male Sprague-Dawley rats | 1–1.5 h daily restraint stress for 8–14 days | 30 min ischemia | Increased IS/AAR% | Scheuer and Mifflin (132) |
| RI 24 h later | 180 min reperfusion | Increased # of fatal arrhythmias | ||
| Adult male Sprague-Dawley rats | 2 h daily restraint stress for 11–12 days | 30 min ischemia | Increased IS/AAR% | Scheuer and Mifflin (132) |
| RI 24 h later | 180 min reperfusion | Increased # of fatal arrhythmias | ||
| Adult male Wistar-Kyoto (WKY) rats | Crowding stress (living space 200 cm2/rat) for 8 weeks | 30 min ischemia | Decreased LVDP recovery | Ravingerova et al. (133) |
| RI unspecified | 120 min reperfusion (reperfusion-induced tachyarrhythmias and contractile function measured 40 min after reperfusion initiation) | Increased duration of ventricular tachycardia (VT) | ||
| Adult male spontaneously hypertensive (SHR) rats | Crowding stress (living space 200 cm2/rat) for 8 weeks | 30 min ischemia | Increased LVDP recovery | Ravingerova et al. (133) |
| RI unspecified | 120 min reperfusion (reperfusion-induced tachyarrhythmias and contractile function measured 40 min after reperfusion initiation) | Decreased duration of VT | ||
| Adult male Wistar rats | 10 s electrical shock, 50 s rest for 1 h daily for 7 days | 30 min ischemia | Increased IS/AAR% | Rakhshan et al. (10) |
| RI 24 h later | 120 min reperfusion | |||
| Adult male Wistar rats | Witnessed rats receive but did not receive 10 s electrical shock, 50 s rest for 1 h daily for 7 days (psychological shock) | 30 min ischemia | Increased IS/AAR% | Rakhshan et al. (10) |
| RI 24 h later | 120 min reperfusion | |||
| 5-week-old male Wistar-Kyoto (WKY) rats | Crowding stress (~70 cm2 living space per 100g body mass) for 14 days | 30 min ischemia | No significant difference between stress and no stress groups | Ledvenyiova-Farkasova et al. (134) |
| RI unspecified | 120 min reperfusion (reperfusion-induced tachyarrhythmias and contractile function measured 40 min after reperfusion initiation) | |||
| 5-week-old female Wistar-Kyoto (WKY) rats | Crowding stress (~70 cm2 living space per 100 g body mass) for 14 days | 30 min ischemia | Decreased VT duration | Ledvenyiova-Farkasova et al. (134) |
| RI unspecified | 120 min reperfusion (reperfusion-induced tachyarrhythmias and contractile function measured 40 min after reperfusion initiation) | |||
| 5-week-old female spontaneously hypertensive (SHR) rats | Crowding stress (~70 cm2 living space per 100 g body mass) for 14 days | 30 min ischemia | Increased VT duration | Ledvenyiova-Farkasova et al. (134) |
| RI unspecified | 120 min reperfusion (reperfusion-induced tachyarrhythmias and contractile function measured 40 min after reperfusion initiation) | |||
| 5-week-old male spontaneously hypertensive (SHR) rats | Crowding stress (~70 cm2 living space per 100 g body mass) for 14 days | 30 min ischemia | Increased VT duration | Ledvenyiova-Farkasova et al. (134) |
| RI unspecified | 120 min reperfusion (reperfusion-induced tachyarrhythmias and contractile function measured 40 min after reperfusion initiation) | |||
| Adult male Sprague-Dawley rats | 31 days chronic social instability (randomized paired housing) | 20 min ischemia | Increased IS/AAR% | Rorabaugh et al. (135) |
| 1 h immobilized predator exposure on days 1 and 11 | 120 min reperfusion | Decreased RPP | ||
| See Zoladz et al. (136) for complete PTSD paradigm RI 48 h later | Decreased + dP/dT | |||
| Adult female Sprague-Dawley rats | 31 days chronic social instability (randomized paired housing) | 20 min ischemia | No significant effect | Rorabaugh et al. (135) |
| 1 h immobilized predator exposure on days 1 and 11 | 120 min reperfusion | |||
| See Zoladz et al. (136) for complete PTSD paradigm | ||||
| RI 48 h after | ||||
Studies examining myocardial ischemic injury in rodent models of psychological stress.
Research has previously shown that short-term stress is accompanied by enhanced contractile function and resistance to hypoxia in hearts isolated from stressed animals, while long-term stress resulted in the opposite effect (4, 7). Additionally, acute stressors seem to result in the redistribution of the immune system to the site of inflammation, which could provide an adaptive response to stress (137–139). Interestingly, opioid antagonists were able to eliminate the cardioprotection afforded by cold-restraint stress, supporting this stress-limiting system’s role in decreased sensitivity to ischemic damage (113, 117, 140).
Though acute psychological stress decreases the sensitivity of ischemic damage in response to myocardial IRI, the work does not necessarily contradict the previously discussed, well-established effects of acute stress in both animal models and clinical research, including triggering MI or independently leading to ischemic damage (72–75, 100–103). While electrical instability of the heart occurs in response to acute stress, it is possible that protective pathways exist to reduce the sensitivity to ischemic damage (4, 7, 116, 140). Additionally, it is important to recognize that while removing the additional stressors and underlying pathology found in humans adds experimental control, it does diminish the clinical translatability of this work (33, 52, 53). Furthermore, while investigators look at the myocardial ischemic injury of all rodents exposed to acute psychological stress, MI data in humans in response to acute stressors typically only represent patients who experienced an MI or symptoms of an MI (72–75). As a final potential limitation, rodent models look at the same ischemic injury in all subjects, whereas human patients can present with very different ischemic damage due to underlying disease and the possible collateralization of vessels over many years (135).
Contrasting the protective effects of acute stress, chronic stress in rodent models has impacted sensitivity to myocardial ischemic injury in rodent models by decreasing recovery of cardiac contractility and increasing ischemic injury (10, 132, 133, 134). The effect of chronic psychological stress is especially relevant because of the numerous stressors facing human patients, which have effects on cardiovascular outcomes (8, 14, 17–22, 141, 142). Thus, diminishing the negative effects of chronic stress on the heart has the ability to reduce cardiovascular morbidity and mortality. Therefore, the effect of chronic stress on the cardiovascular system has been an emerging area of research with several recent studies looking directly at myocardial ischemic injury.
Chronic Stress and Cardiovascular Disease
Chronic stress has been implicated to cause or worsen CVD in human patients (20, 141–145). Chronic stress has been linked to increased risk of ischemic heart disease (20, 28). The INTERHEART case–control study showed that significant long-term stress over the course of 12 months more than doubled the risk of acute MI, even after adjusting for conventional risk factors such as diabetes mellitus, hypertension, and smoking (146). Prospective cohort studies have supported the effect of long-term stress on risk of coronary heart disease. Studies have linked coronary heart disease risk with work-related stressors, specifically when an imbalance between effort and reward is experienced (147–151). Furthermore, the effects of long-term stress may persist long after the cessation of the chronic stressors. Survivors of the siege of Leningrad were found to have increased blood pressure and increased mortality from CVD, relative to Russians who were not in the besieged city, over 50 years after the event (152).
Chronic Stress and Cardiovascular Disease
Psychological conditions related to chronic stress and CVD include depression, anxiety, and PTSD (3). As previously discussed, psychiatric disorders can worsen outcomes in CVD. However, this relationship may be bidirectional. For example, it has been shown that coronary heart disease leads to a higher incidence of depression, and depression leads to worse outcomes in coronary heart disease (14, 15, 17, 49, 153). Furthermore, the association between depression and coronary heart disease occurs independent of comorbid risk factors such as high cholesterol, hypertension, or obesity (13, 49, 154, 155). PTSD also increases a patient’s risk for developing coronary heart disease. This association is independent of comorbid depression, genetic influences, and other confounding factors (156–158). The negative cardiovascular outcomes exhibited in both depression and PTSD have been attributed to underlying dysfunction in the autonomic nervous system and HPA axis (13, 22, 48, 49, 135). However, precisely defining the contribution of long-term stress to CVD is difficult due to potential confounding factors including the aforementioned psychological disorders (28). Thus, animal models provide an acceptable means to study chronic stress in the controlled experimental setting (22).
Experimental Chronic Stress and Cardiovascular Disease
Animal models support the negative effects of chronic stress on the cardiovascular system evidenced by epidemiological studies. Experimental studies have found exposure to chronic stress results in enhanced development of atherosclerosis and plaque destabilization (3, 159, 160). Chronic stress has also been shown to lower the threshold for ventricular arrhythmias (103, 107–109, 161, 162). In a landmark study, Verrier and Lown conditioned dogs to associate a sling with an aversive shock for 3 days. On days 4 and 5, these researchers found that coronary occlusion in dogs re-exposed to the sling environment (in the absence of shock) led to ventricular fibrillation, whereas dogs in a non-aversive cage environment did not experience ventricular fibrillation. Research has continued to focus on this ability of chronic psychological stress to result in cardiac instability (101, 102, 107).
Researchers have used validated models of psychological disorders to study the relationship between psychological disorders and the cardiovascular system. For example, the relationship between depression and CVD has been studied using chronic stress models [e.g., chronic mild stress (CMS) and social isolation] of depression in rodents. The CMS model of depression involves exposure to mild and unpredictable stressors, including changing cage mates, cage tilt, and periods of water or food deprivation, for a period greater than 2 weeks (49, 153, 163). These models of depression decrease rodent intake of a sweet solution, suggestive of anhedonia. Rodents exposed to these well-established animal models display depressive-like behavior, and have a decreased threshold for arrhythmias and tissue fibrosis (22, 49, 153, 163–167). Although animal models have been used to study stress biology and cardiovascular outcomes, few studies exist using validated models of psychological disorders to study the effect of stress on sensitivity to myocardial ischemic injury.
Experimental Chronic Stress and Myocardial Ischemic Injury
In several recent rodent studies, researchers have found greater ISs, decreased cardiac output, and decreased recovery of contractile function in response to chronic psychological stress [see Table 1 (10, 132, 133, 134, 135)]. Chronic physiologic stress has previously shown mixed results; both decreased (168) and increased (169) sensitivity to myocardial ischemic injury have been reported. Evidencing only negative effects of chronic stress on myocardial ischemic injury, the impact of chronic psychological stress represents an emerging area of research to minimize the detrimental effect of chronic stress (135, 170). The disruptive effect of chronic psychological stress exposure on myocardial ischemic injury has been demonstrated using several different chronic stressors, including chronic restraint stress (132), daily foot shocks or witnessing rats receiving those foot shocks (10), or crowding stress (133, 134).
These stressors are frequently utilized in modeling psychological disorders that result from stress. Restraint stress has been used as a psychological stressor in rats and has been utilized in combination with other stressors to model PTSD and depression (119, 122, 123, 136). Inescapable footshock is used to model depressive symptoms in rodents. Rats exposed to inescapable footshock have demonstrated anxiety-like behavior on an EPM, impaired growth rates, decreased rearing in an open field, and decreased locomotion (50, 171–173). Crowding stress is a well-known and ethologically valid model of psychological stress in rats which causes social competition for resources, such as space, food, and water. Crowding stress results in behavioral and physiologic data reflecting psychological stress (174–178). These chronic psychological stressors resulted in disruption to the cardiovascular system following induced myocardial ischemic injury, either by causing increased IS and decreased contractile function recovery (10, 132) or only decreased contractile function recovery (133, 134). These studies suggest that chronic stress not only increases the likelihood of a MI or SCD but also exacerbates the damage in response to ischemic injury.
A potential limitation of these studies is that researchers did not take behavioral measures of stress prior to myocardial ischemic injury. Although the methods of stress used to stress these animals are validated as methods of inducing psychological stress, individual susceptibility may play a role in the response of the animal to a psychological stressor (10, 132, 133, 134). Stress exposure may affect animals differently, and thus, measurement of the stress response at the behavioral level is important. The only known published study utilizing a model of a chronic psychological disorder where animals’ response to stress was validated prior to myocardial ischemic injury is utilizing a predator-based psychosocial model of PTSD (135).
A Predator-Based Psychosocial Model of PTSD and Myocardial Ischemia–Reperfusion Injury
A predator-based psychosocial model of PTSD has been utilized to study sensitivity to myocardial ischemic injury. This model involves two 1-h cat exposures, during which rats are restrained while they can see, smell, and hear a cat but cannot be physically harmed. The two exposures are separated by a period of 10 days. Starting on the day of the first cat exposure, rodents experience chronic social instability by having their housing partner changed daily for 31 days. After the 31-day paradigm, rats exhibit a fear memory associated with the cat exposures (evidenced by freezing in response to conditioned context and cues), heightened anxiety-like behavior on the EPM, an exaggerated startle response, and impaired memory for newly learned information. Furthermore, rats exposed to this paradigm have demonstrated physiological changes reflecting elevated SNS activity and HPA axis abnormalities, including elevated heart rate and blood pressure, decreased baseline corticosterone levels, and enhanced negative feedback of the HPA axis (135, 136, 179–181). Replicating and expanding on these results, researchers utilizing this model have shown stressed rats exhibit decreased serotonin, increased norepinephrine, and increased measures of oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation (182, 183).
Recently, we found that, subsequent to this chronic psychological stress paradigm, male rats exposed to myocardial ischemic injury exhibited greater ISs and decreased recovery of contractile function [Figure 1 (135)]. The disruptive effect of this PTSD paradigm on the heart is further strengthened by anxiety-like behavior in rats on the EPM prior to myocardial ischemic injury. These data suggest that the psychological stress induced by the PTSD paradigm is having an effect directly on the heart, causing the heart to be more susceptible to damage following a MI (135). The ability of chronic stress to worsen the extent of ischemic injury and decrease the recovery of cardiac contractility further exacerbates the supported negative effects of stress in CVD, which make rodents exposed to chronic stress more susceptible to ventricular fibrillation and MI (13, 22, 48, 49, 135).
Figure 1
The Importance of the Effect of Psychological Stress on Myocardial Ischemia–Reperfusion Injury
Shown presently, acute and chronic psychological stress affects sensitivity to myocardial ischemic injury in opposite directions; acute psychological stress decreases, whereas chronic psychological stress increases sensitivity to myocardial ischemic injury (45, 117). It is possible that protective mechanisms exist in response to an optimal level of acute stress, but these mechanisms are eventually overcome by more intense levels of stress (4).
Physiologically, a possible explanation for this differential effect is that acute psychological stress causes norepinephrine release and acute alpha stimulation, which results in ischemic preconditioning (184, 185). Chronic psychological stress may result in chronic beta stimulation, worsening the ischemic injury (186–190). The previously discussed advantages of the isolated rat heart (66), the wide variety of validated psychological stressors in rodents (119, 122, 123, 136, 174–178), and the existence of rodent models of psychiatric disorders (49, 153, 181) add weight to the presently discussed findings. However, it is important to qualify these findings by recognizing the methodological differences in a limited amount of studies and the previously discussed weaknesses of translating the isolated rodent heart to humans.
Utilizing ethologically valid models of stress to further study the effect of psychological stress on myocardial ischemic injury will best translate to improving patient outcomes in the clinical setting (22, 49). Additionally, further research investigating the effects of stress on the cardiovascular system in females will be important in translating findings to the clinical setting, as the current literature is currently dominated by studies in male subjects (135).
Conclusion
The relationship between stress and CVD continues to receive a substantial amount of attention. Here, we reviewed research studying the sensitivity of the rodent heart to ischemic injury in response acute and chronic psychological stress in the context of clinical and experimental studies on the effects of stress on the cardiovascular system. Elucidation of stress-limiting systems will help identify novel therapeutic options to decrease cardiovascular mortality. Further research investigating the relationship between acute and chronic stress and ischemic injury will improve patient care with implications that extend beyond cardiovascular disease.
Statements
Author contributions
EE wrote the first draft of the manuscript and revised it following peer review. BR provided comments on each draft. PZ helped EE prepare the manuscript, provided comments on each draft, and prepared the figures.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
CannonWB. Stresses and strains of homeostasis. Am J Med Sci (1935) 189(1):13–4.10.1097/00000441-193501000-00001
2
SelyeH. The story of the adaptation syndrome. Am J Med Sci (1952) 224(6):711.10.1097/00000441-195212000-00039
3
LagraauwHMKuiperJBotI. Acute and chronic psychological stress as risk factors for cardiovascular disease: insights gained from epidemiological, clinical and experimental studies. Brain Behav Immun (2015) 50:18–30.10.1016/j.bbi.2015.08.007
4
MeersonFZ. Stress-induced arrhythmic disease of the heart – part I. Clin Cardiol (1994) 17(7):362–71.10.1002/clc.4960170705
5
McEwenBS. Protective and damaging effects of stress mediators. N Engl J Med (1998) 338(3):171–9.10.1056/NEJM199801153380307
6
MeijerOC. Understanding stress through the genome. Stress (2006) 9(2):61–7.10.1080/10253890600799669
7
MeersonFZ. Adaptive Protection of the Heart. Boca Raton, FL: CRC Press (1990).
8
DimsdaleJE. Psychological stress and cardiovascular disease. J Am Coll Cardiol (2008) 51(13):1237–46.10.1016/j.jacc.2007.12.024
9
JohnsonEOKamilarisTCChrousosGPGoldPW. Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis. Neurosci Biobehav Rev (1992) 16(2):115–30.10.1016/S0149-7634(05)80175-7
10
RakhshanKImaniAFaghihiMNabavizadehFGolnazariMKarimianS. Evaluation of chronic physical and psychological stress induction on cardiac ischemia/reperfusion injuries in isolated male rat heart: the role of sympathetic nervous system. Acta Med Iran (2015) 53(8):482–90.
11
TennantCLangeluddeckePByrneD. The concept of stress. Aust N Z J Psychiatry (1985) 19(2):113–8.10.3109/00048678509161308
12
ParkerGBOwenCABrotchieHLHyettMP. The impact of differing anxiety disorders on outcome following an acute coronary syndrome: time to start worrying?Depress Anxiety (2010) 27(3):302–9.10.1002/da.20602
13
PenninxBWBeekmanATHonigADeegDJSchoeversRAvan EijkJTet alDepression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry (2001) 58(3):221–7.10.1001/archpsyc.58.3.221
14
AndaRWilliamsonDJonesDMaceraCEakerEGlassmanAet alDepressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology (1993) 4(4):285–94.10.1097/00001648-199307000-00003
15
MavridesNNemeroffC. Treatment of depression in cardiovascular disease. Depress Anxiety (2013) 30(4):328–41.10.1002/da.22051
16
MavridesNNemeroffCB. Treatment of affective disorders in cardiac disease. Dialogues Clin Neurosci (2015) 17(2):127–40.
17
BarefootJCHelmsMJMarkDBBlumenthalJACaliffRMHaneyTLet alDepression and long-term mortality risk in patients with coronary artery disease. Am J Cardiol (1996) 78(6):613–7.10.1016/S0002-9149(96)00380-3
18
KettererMW. Secondary prevention of ischemic heart disease. The case for aggressive behavioral monitoring and intervention. Psychosomatics (1993) 34(6):478–84.10.1016/S0033-3182(93)71821-6
19
MonroeSMHarknessKL. Life stress, the “kindling” hypothesis, and the recurrence of depression: considerations from a life stress perspective. Psychol Rev (2005) 112(2):417–45.10.1037/0033-295X.112.2.417
20
SteptoeAKivimakiM. Stress and cardiovascular disease: an update on current knowledge. Annu Rev Public Health (2013) 34:337–54.10.1146/annurev-publhealth-031912-114452
21
SwaabDFBaoAMLucassenPJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev (2005) 4(2):141–94.10.1016/j.arr.2005.03.003
22
GrippoAJ. The utility of animal models in understanding links between psychosocial processes and cardiovascular health. Soc Personal Psychol Compass (2011) 5(4):164–79.10.1111/j.1751-9004.2011.00342.x
23
GianarosPJWagerTD. Brain-body pathways linking psychological stress and physical health. Curr Dir Psychol Sci (2015) 24(4):313–21.10.1177/0963721415581476
24
RichtigETrappEMAvianABrezinsekHPTrappMEggerJWet alPsychological stress and immunological modulations in early-stage melanoma patients. Acta Derm Venereol (2015) 95(6):691–5.10.2340/00015555-2045
25
DaveyAShuklaASharmaPSrivastavaKDaveySVyasS. Are the adverse psychiatric outcomes reflection of occupational stress among nurses: an exploratory study. Asian J Med Sci (2016) 7(1):96–100.10.3126/ajms.v7i1.12869
26
MathersCDLoncarD. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med (2006) 3(11):e442.10.1371/journal.pmed.0030442
27
QuamLSmithRYachD. Rising to the global challenge of the chronic disease epidemic. Lancet (2006) 368(9543):1221–3.10.1016/S0140-6736(06)69422-1
28
SteptoeAKivimakiM. Stress and cardiovascular disease. Nat Rev Cardiol (2012) 9(6):360–70.10.1038/nrcardio.2012.45
29
GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (2015) 385(9963):117–71.10.1016/S0140-6736(14)61682-2
30
MendisSPuskaPNorrvingB. Global Atlas on Cardiovascular Disease Prevention and Control. Geneva: World Health Organization (2011).
31
JanseMJ. Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovasc Res (2004) 61(2):208–17.10.1016/j.cardiores.2003.11.018
32
JanseMJWitAL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev (1989) 69(4):1049–169.
33
BraunwaldEKlonerRA. Myocardial reperfusion: a double-edged sword?J Clin Invest (1985) 76(5):1713–9.10.1172/JCI112160
34
EeftingFRensingBWigmanJPannekoekWJLiuWMCramerMJet alRole of apoptosis in reperfusion injury. Cardiovasc Res (2004) 61(3):414–26.10.1016/j.cardiores.2003.12.023
35
FrankABonneyMBonneySWeitzelLKoeppenMEckleT. Myocardial ischemia reperfusion injury: from basic science to clinical bedside. Semin Cardiothorac Vasc Anesth (2012) 16(3):123–32.10.1177/1089253211436350
36
GottliebRABurlesonKOKlonerRABabiorBMEnglerRL. Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest (1994) 94(4):1621–8.10.1172/JCI117504
37
RaoPRKumarVKViswanathRKSubbarajuGV. Cardioprotective activity of alcoholic extract of Tinospora cordifolia in ischemia-reperfusion induced myocardial infarction in rats. Biol Pharm Bull (2005) 28(12):2319–22.10.1248/bpb.28.2319
38
WangQDSwardhASjoquistPO. Relationship between ischaemic time and ischaemia/reperfusion injury in isolated Langendorff-perfused mouse hearts. Acta Physiol Scand (2001) 171(2):123–8.10.1046/j.1365-201x.2001.00788.x
39
JenningsRBSommersHMSmythGAFlackHALinnH. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Arch Pathol (1960) 70:68–78.
40
McMichaelMMooreRM. Ischemia-reperfusion injury pathophysiology, part I. J Vet Emerg Crit Care (2004) 14(4):231–41.10.1111/j.1476-4431.2004.04004.x
41
TaggartPCritchleyHLambiasePD. Heart-brain interactions in cardiac arrhythmia. Heart (2011) 97(9):698–708.10.1136/hrt.2010.209304
42
VerrierRL. Behavioral stress, myocardial ischemia, and arrhythmias. In: ZipesDPJalifeJ, editors. Cardiac Electrophysiology: From Cell to Bedside. Toronto: WB Saunders (1990). p. 343–52.
43
KocogluHKaraaslanKGoncaEBozdoganOGulcuN. Preconditioning effects of dexmedetomidine on myocardial ischemia/reperfusion injury in rats. Curr Ther Res Clin Exp (2008) 69(2):150–8.10.1016/j.curtheres.2008.04.003
44
MiricaSNOrdodiVApostolAAnaDRăducanADuicuOet alLangendorff perfused heart – the 110 years old experimental model that gets better with age. Studia Univ Vasile Goldis Seria Stiintele Vietii (2009) 19(1):81–6.
45
MoghimianMFaghihiMKarimianSMImaniA. The effect of acute stress exposure on ischemia and reperfusion injury in rat heart: role of oxytocin. Stress (2012) 15(4):385–92.10.3109/10253890.2011.630436
46
MurphyESteenbergenC. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev (2008) 88(2):581–609.10.1152/physrev.00024.2007
47
NeumannIDWegenerGHombergJRCohenHSlatteryDAZoharJet alAnimal models of depression and anxiety: what do they tell us about human condition?Prog Neuropsychopharmacol Biol Psychiatry (2011) 35(6):1357–75.10.1016/j.pnpbp.2010.11.028
48
ZoladzPRDiamondDM. Current status on behavioral and biological markers of PTSD: a search for clarity in a conflicting literature. Neurosci Biobehav Rev (2013) 37(5):860–95.10.1016/j.neubiorev.2013.03.024
49
GrippoAJ. Mechanisms underlying altered mood and cardiovascular dysfunction: the value of neurobiological and behavioral research with animal models. Neurosci Biobehav Rev (2009) 33(2):171–80.10.1016/j.neubiorev.2008.07.004
50
LiHZhouCChenDFangNYaoYLiL. Failure to protect against myocardial ischemia-reperfusion injury with sevoflurane postconditioning in old rats in vivo. Acta Anaesthesiol Scand (2013) 57(8):1024–31.10.1111/aas.12156
51
NagataTYasukawaHKyogokuSObaTTakahashiJNoharaSet alCardiac-specific SOCS3 deletion prevents in vivo myocardial ischemia reperfusion injury through sustained activation of cardioprotective signaling molecules. PLoS One (2015) 10(5):e0127942.10.1371/journal.pone.0127942
52
BellRMMocanuMMYellonDM. Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol (2011) 50(6):940–50.10.1016/j.yjmcc.2011.02.018
53
Skrzypiec-SpringMGrotthusBSzelagASchulzR. Isolated heart perfusion according to Langendorff – still viable in the new millennium. J Pharmacol Toxicol Methods (2007) 55(2):113–26.10.1016/j.vascn.2006.05.006
54
YeJXChenDZ. Novel cardioprotective strategy combining three different preconditioning methods to prevent ischemia/reperfusion injury in aged hearts in an improved rabbit model. Exp Ther Med (2015) 10(4):1339–47.10.3892/etm.2015.2680
55
SuzukiYYeungACIkenoF. The pre-clinical animal model in the translational research of interventional cardiology. JACC Cardiovasc Interv (2009) 2(5):373–83.10.1016/j.jcin.2009.03.004
56
VidavalurRSwarnakarSThirunavukkarasuMSamuelSMMaulikN. Ex vivo and in vivo approaches to study mechanisms of cardioprotection targeting ischemia/reperfusion (i/r) injury: useful techniques for cardiovascular drug discovery. Curr Drug Discov Technol (2008) 5(4):269–78.10.2174/157016308786733555
57
YtrehusK. The ischemic heart – experimental models. Pharmacol Res (2000) 42(3):193–203.10.1006/phrs.2000.0669
58
HillAJLaskeTGColesJAJrSiggDCSkadsbergNDVincentSAet alIn vitro studies of human hearts. Ann Thorac Surg (2005) 79(1):168–77.10.1016/j.athoracsur.2004.06.080
59
SutherlandFJHearseDJ. The isolated blood and perfusion fluid perfused heart. Pharmacol Res (2000) 41(6):613–27.10.1006/phrs.1999.0653
60
HearseDJSutherlandFJ. Experimental models for the study of cardiovascular function and disease. Pharmacol Res (2000) 41(6):597–603.10.1006/phrs.1999.0651
61
VerdouwPDvan den DoelMAde ZeeuwSDunckerDJ. Animal models in the study of myocardial ischaemia and ischaemic syndromes. Cardiovasc Res (1998) 39(1):121–35.10.1016/S0008-6363(98)00069-8
62
MaxwellMPHearseDJYellonDM. Species variation in the coronary collateral circulation during regional myocardial ischaemia: a critical determinant of the rate of evolution and extent of myocardial infarction. Cardiovasc Res (1987) 21(10):737–46.10.1093/cvr/21.10.737
63
JohnsTNOlsonBJ. Experimental myocardial infarction. I. A method of coronary occlusion in small animals. Ann Surg (1954) 140(5):675–82.10.1097/00000658-195411000-00006
64
DaySBJohnsonJA. The distribution of the coronary arteries of the rabbit. Anat Rec (1958) 132(4):633–43.10.1002/ar.1091320411
65
ReesSACurtisMJ. Selective IK blockade as an antiarrhythmic mechanism: effects of UK66, 914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts. Br J Pharmacol (1993) 108(1):139–45.10.1111/j.1476-5381.1993.tb13453.x
66
CurtisMJ. Characterisation, utilisation and clinical relevance of isolated perfused heart models of ischaemia-induced ventricular fibrillation. Cardiovasc Res (1998) 39(1):194–215.10.1016/S0008-6363(98)00083-2
67
ReesSACurtisMJ. Specific IK1 blockade: a new antiarrhythmic mechanism? Effect of RP58866 on ventricular arrhythmias in rat, rabbit, and primate. Circulation (1993) 87(6):1979–89.10.1161/01.CIR.87.6.1979
68
CurtisMJMacleodBAWalkerMJ. Models for the study of arrhythmias in myocardial ischaemia and infarction: the use of the rat. J Mol Cell Cardiol (1987) 19(4):399–419.10.1016/S0022-2828(87)80585-0
69
FengXTaggartPHallLBryantSSansoneJKemmererMet alLimited additional release of cardiac troponin I and T in isoproterenol-treated beagle dogs with cardiac injury. Clin Chem (2005) 51(7):1305–7.10.1373/clinchem.2005.049643
70
BleuelHDeschlUBertschTBolzGRebelW. Diagnostic efficiency of troponin T measurements in rats with experimental myocardial cell damage. Exp Toxicol Pathol (1995) 47(2–3):121–7.10.1016/S0940-2993(11)80297-6
71
SteinbergJSArshadAKowalskiMKukarASumaVVlokaMet alIncreased incidence of life-threatening ventricular arrhythmias in implantable defibrillator patients after the World Trade Center attack. J Am Coll Cardiol (2004) 44(6):1261–4.10.1016/j.jacc.2004.06.032
72
SteptoeABrydonL. Emotional triggering of cardiac events. Neurosci Biobehav Rev (2009) 33(2):63–70.10.1016/j.neubiorev.2008.04.010
73
ChanCElliottJTroughtonRFramptonCSmythDCrozierIet alAcute myocardial infarction and stress cardiomyopathy following the Christchurch earthquakes. PLoS One (2013) 8(7):e68504.10.1371/journal.pone.0068504
74
MollerJTheorellTde FaireUAhlbomAHallqvistJ. Work related stressful life events and the risk of myocardial infarction. Case-control and case-crossover analyses within the Stockholm heart epidemiology programme (SHEEP). J Epidemiol Community Health (2005) 59(1):23–30.10.1136/jech.2003.019349
75
MittlemanMAMaclureMSherwoodJBMulryRPToflerGHJacobsSCet alTriggering of acute myocardial infarction onset by episodes of anger. Determinants of Myocardial Infarction Onset Study Investigators. Circulation (1995) 92(7):1720–5.10.1161/01.CIR.92.7.1720
76
KrantzDSKopWJSantiagoHTGottdienerJS. Mental stress as a trigger of myocardial ischemia and infarction. Cardiol Clin (1996) 14(2):271–87.10.1016/S0733-8651(05)70280-0
77
BrotmanDJGoldenSHWittsteinIS. The cardiovascular toll of stress. Lancet (2007) 370(9592):1089–100.10.1016/S0140-6736(07)61305-1
78
WittsteinISThiemannDRLimaJABaughmanKLSchulmanSPGerstenblithGet alNeurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med (2005) 352(6):539–48.10.1056/NEJMoa043046
79
SharkeySWWindenburgDCLesserJRMaronMSHauserRGLesserJNet alNatural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol (2010) 55(4):333–41.10.1016/j.jacc.2009.08.057
80
EngelGL. Sudden and rapid death during psychological stress. Folklore or folk wisdom?Ann Intern Med (1971) 74(5):771–82.10.7326/0003-4819-74-5-771
81
EngelGL. Psychologic stress, vasodepressor (vasovagal) syncope, and sudden death. Ann Intern Med (1978) 89(3):403–12.10.7326/0003-4819-89-3-403
82
AkashiYJNefHMMollmannHUeyamaT. Stress cardiomyopathy. Annu Rev Med (2010) 61:271–86.10.1146/annurev.med.041908.191750
83
TsuchihashiKUeshimaKUchidaTOh-muraNKimuraKOwaMet alTransient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. Angina Pectoris-Myocardial Infarction Investigations in Japan. J Am Coll Cardiol (2001) 38(1):11–8.10.1016/S0735-1097(01)01316-X
84
RozanskiABaireyCNKrantzDSFriedmanJResserKJMorellMet alMental stress and the induction of silent myocardial ischemia in patients with coronary artery disease. N Engl J Med (1988) 318(16):1005–12.10.1056/NEJM198804213181601
85
DeanfieldJESheaMKensettMHorlockPWilsonRAde LandsheereCMet alSilent myocardial ischaemia due to mental stress. Lancet (1984) 2(8410):1001–5.10.1016/S0140-6736(84)91106-1
86
PimplePShahARooksCBremnerJDNyeJIbeanuIet alAssociation between anger and mental stress-induced myocardial ischemia. Am Heart J (2015) 169(1):115.e–21.e.10.1016/j.ahj.2014.07.031
87
BurgMMJainDSouferRKernsRDZaretBL. Role of behavioral and psychological factors in mental stress-induced silent left ventricular dysfunction in coronary artery disease. J Am Coll Cardiol (1993) 22(2):440–8.10.1016/0735-1097(93)90048-6
88
GottdienerJSKrantzDSHowellRHHechtGMKleinJFalconerJJet alInduction of silent myocardial ischemia with mental stress testing: relation to the triggers of ischemia during daily life activities and to ischemic functional severity. J Am Coll Cardiol (1994) 24(7):1645–51.10.1016/0735-1097(94)90169-4
89
BeckerLCPepineCJBonsallRCohenJDGoldbergADCoghlanCet alLeft ventricular, peripheral vascular, and neurohumoral responses to mental stress in normal middle-aged men and women. Reference Group for the Psychophysiological Investigations of Myocardial Ischemia (PIMI) study. Circulation (1996) 94(11):2768–77.10.1161/01.CIR.94.11.2768
90
StrikePCSteptoeA. Systematic review of mental stress-induced myocardial ischaemia. Eur Heart J (2003) 24(8):690–703.10.1016/S0195-668X(02)00615-2
91
YeungACVekshteinVIKrantzDSVitaJARyanTJJrGanzPet alThe effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med (1991) 325(22):1551–6.10.1056/NEJM199111283252205
92
RosenbaumDSJacksonLESmithJMGaranHRuskinJNCohenRJ. Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med (1994) 330(4):235–41.10.1056/NEJM199401273300402
93
KopWJKrantzDSNearingBDGottdienerJSQuigleyJFO’CallahanMet alEffects of acute mental stress and exercise on T-wave alternans in patients with implantable cardioverter defibrillators and controls. Circulation (2004) 109(15):1864–9.10.1161/01.CIR.0000124726.72615.60
94
KovachJANearingBDVerrierRL. Angerlike behavioral state potentiates myocardial ischemia-induced T-wave alternans in canines. J Am Coll Cardiol (2001) 37(6):1719–25.10.1016/S0735-1097(01)01196-2
95
TaggartPSuttonPChalabiZBoyettMRSimonRElliottDet alEffect of adrenergic stimulation on action potential duration restitution in humans. Circulation (2003) 107(2):285–9.10.1161/01.CIR.0000044941.13346.74
96
ChildNHansonBBishopMRinaldiCABostockJWesternDet alEffect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate. Circ Arrhythm Electrophysiol (2014) 7(3):518–23.10.1161/CIRCEP.113.000909
97
BradleyCPClaytonRHNashMPMouradAHaywardMPatersonDJet alHuman ventricular fibrillation during global ischemia and reperfusion: paradoxical changes in activation rate and wavefront complexity. Circ Arrhythm Electrophysiol (2011) 4(5):684–91.10.1161/CIRCEP.110.961284
98
KazbanovIVClaytonRHNashMPBradleyCPPatersonDJHaywardMPet alEffect of global cardiac ischemia on human ventricular fibrillation: insights from a multi-scale mechanistic model of the human heart. PLoS Comput Biol (2014) 10(11):e1003891.10.1371/journal.pcbi.1003891
99
LownB. Sudden cardiac death: the major challenge confronting contemporary cardiology. Am J Cardiol (1979) 43(2):313–28.10.1016/S0002-9149(79)80021-1
100
LownB. Sudden cardiac death: biobehavioral perspective. Circulation (1987) 76(1 Pt 2):I186–96.
101
LownBTemteJVReichPGaughanCRegesteinQHalH. Basis for recurring ventricular fibrillation in the absence of coronary heart disease and its management. N Engl J Med (1976) 294(12):623–9.10.1056/NEJM197603182941201
102
LownBVerrierRLRabinowitzSH. Neural and psychologic mechanisms and the problem of sudden cardiac death. Am J Cardiol (1977) 39(6):890–902.10.1016/S0002-9149(77)80044-1
103
VerrierRLHagestadELLownB. Delayed myocardial ischemia induced by anger. Circulation (1987) 75(1):249–54.10.1161/01.CIR.75.1.249
104
SkinnerJEReedJC. Blockade of frontocortical-brain stem pathway prevents ventricular fibrillation of ischemic heart. Am J Physiol (1981) 240(2):H156–63.
105
CorbalanRVerrierRLownB. Psychological stress and ventricular arrhythmias during myocardial infarction in the conscious dog. Am J Cardiol (1974) 34(6):692–6.10.1016/0002-9149(74)90159-3
106
LownBVerrierRCorbalanR. Psychologic stress and threshold for repetitive ventricular response. Science (1973) 182(4114):834–6.10.1126/science.182.4114.834
107
VerrierRLLownB. Influence of neural activity on ventricular electrical instability during acute myocardial ischemia and infarction. In: SandoeEJulianDGBellJW, editors. Management of Ventricular Tachycardia-Role of Mexiletine. Amsterdam: Excerpta Medica (International Congress Series No. 458) (1978). p. 133–50.
108
VerrierRLLownB. Behavioral stress and cardiac arrhythmias. Annu Rev Physiol (1984) 46:155–76.10.1146/annurev.ph.46.030184.001103
109
VerrierRLombardiFLownB, editors. Restraint of myocardial blood-flow during behavioral stress. Circulation. Dallas: American Heart Association (1982).
110
AdameovaAAbdellatifYDhallaNS. Role of the excessive amounts of circulating catecholamines and glucocorticoids in stress-induced heart disease. Can J Physiol Pharmacol (2009) 87(7):493–514.10.1139/y09-042
111
GillisR. Neurotransmitters involved in the central nervous-system control of cardiovascular function. Dev Neurosci (1982) 15:41–53.
112
SegalSAJacobTGillisRA. Blockade of central nervous system GABAergic tone causes sympathetic-mediated increases in coronary vascular resistance in cats. Circ Res (1984) 55(3):404–15.10.1161/01.RES.55.3.404
113
PasykSWaltonJPittB, editors. Central opioid mediated coronary and systemic vasoconstriction in the conscious dog. Circulation. Dallas: American Heart Association (1981).
114
KentKMSmithERRedwoodDREpsteinSE. Electrical stability of acutely ischemic myocardium. Influences of heart rate and vagal stimulation. Circulation (1973) 47(2):291–8.10.1161/01.CIR.47.2.291
115
DeSilvaRAVerrierRLLownB. The effects of psychological stress and vagal stimulation with morphine on vulnerability to ventricular fibrillation (VF) in the conscious dog. Am Heart J (1978) 95(2):197–203.10.1016/0002-8703(78)90463-5
116
MeersonFZUstinovaEEManukhinaEB. Prevention of cardiac arrhythmias by adaptation to hypoxia: regulatory mechanisms and cardiotropic effect. Biomed Biochim Acta (1989) 48(2–3):S83–8.
117
WuSWongMCChenMChoCHWongTM. Role of opioid receptors in cardioprotection of cold-restraint stress and morphine. J Biomed Sci (2004) 11(6):726–31.10.1007/BF02254356
118
HavoundjianHPaulSMSkolnickP. Acute, stress-induced changes in the benzodiazepine/gamma-aminobutyric acid receptor complex are confined to the chloride ionophore. J Pharmacol Exp Ther (1986) 237(3):787–93.
119
LiberzonIKrstovMYoungEA. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology (1997) 22(6):443–53.10.1016/S0306-4530(97)00044-9
120
PurdyRHMorrowALMoorePHJrPaulSM. Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci U S A (1991) 88(10):4553–7.10.1073/pnas.88.10.4553
121
SchwartzRDWessMJLabarcaRSkolnickPPaulSM. Acute stress enhances the activity of the GABA receptor-gated chloride ion channel in brain. Brain Res (1987) 411(1):151–5.10.1016/0006-8993(87)90692-5
122
MiaoYLGuoWZShiWZFangWWLiuYLiuJet alMidazolam ameliorates the behavior deficits of a rat posttraumatic stress disorder model through dual 18 kDa translocator protein and central benzodiazepine receptor and neurosteroidogenesis. PLoS One (2014) 9(7):e101450.10.1371/journal.pone.0101450
123
ResstelLBTavaresRFLisboaSFJocaSRCorreaFMGuimaraesFS. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol (2009) 156(1):181–8.10.1111/j.1476-5381.2008.00046.x
124
QianYZShipleyJBLevasseurJEKukrejaRC. Dissociation of heat shock proteins expression with ischemic tolerance by whole body hyperthermia in rat heart. J Mol Cell Cardiol (1998) 30(6):1163–72.10.1006/jmcc.1998.0680
125
TaylorRPHarrisMBStarnesJW. Acute exercise can improve cardioprotection without increasing heat shock protein content. Am J Physiol (1999) 276(3 Pt 2):H1098–102.
126
HoshidaSYamashitaNOtsuKHoriM. Repeated physiologic stresses provide persistent cardioprotection against ischemia-reperfusion injury in rats. J Am Coll Cardiol (2002) 40(4):826–31.10.1016/S0735-1097(02)02001-6
127
JoyeuxMGodin-RibuotDPatelADemengePYellonDMRibuotC. Infarct size-reducing effect of heat stress and alpha1 adrenoceptors in rats. Br J Pharmacol (1998) 125(4):645–50.10.1038/sj.bjp.0702137
128
LockeMTanguayRMKlabundeREIanuzzoCD. Enhanced postischemic myocardial recovery following exercise induction of HSP 72. Am J Physiol (1995) 269(1 Pt 2):H320–5.
129
MurryCEJenningsRBReimerKA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation (1986) 74(5):1124–36.10.1161/01.CIR.74.5.1124
130
DasMDasDK. Molecular mechanism of preconditioning. IUBMB Life (2008) 60(4):199–203.10.1002/iub.31
131
WangGYWuSPeiJMYuXCWongTM. Kappa- but not delta-opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats. Am J Physiol Heart Circ Physiol (2001) 280(1):H384–91.
132
ScheuerDAMifflinSW. Repeated intermittent stress exacerbates myocardial ischemia-reperfusion injury. Am J Physiol (1998) 274(2 Pt 2):R470–5.
133
RavingerovaTBernatovaIMatejikovaJLedvenyiovaVNemcekovaMPechanovaOet alImpaired cardiac ischemic tolerance in spontaneously hypertensive rats is attenuated by adaptation to chronic and acute stress. Exp Clin Cardiol (2011) 16(3):e23–9.
134
Ledvenyiova-FarkasovaVBernatovaIBalisPPuzserovaABartekovaMGablovskyIet alEffect of crowding stress on tolerance to ischemia-reperfusion injury in young male and female hypertensive rats: molecular mechanisms. Can J Physiol Pharmacol (2015) 93(9):793–802.10.1139/cjpp-2015-0026
135
RorabaughBRKrivenkoAEisenmannEDBuiADSeeleySFryMEet alSex-dependent effects of chronic psychosocial stress on myocardial sensitivity to ischemic injury. Stress (2015) 18(6):645–53.10.3109/10253890.2015.1087505
136
ZoladzPRConradCDFleshnerMDiamondDM. Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder. Stress (2008) 11(4):259–81.10.1080/10253890701768613
137
DhabharFSMalarkeyWBNeriEMcEwenBS. Stress-induced redistribution of immune cells – from barracks to boulevards to battlefields: a tale of three hormones – Curt Richter Award winner. Psychoneuroendocrinology (2012) 37(9):1345–68.10.1016/j.psyneuen.2012.05.008
138
ViswanathanKDhabharFS. Stress-induced enhancement of leukocyte trafficking into sites of surgery or immune activation. Proc Natl Acad Sci U S A (2005) 102(16):5808–13.10.1073/pnas.0501650102
139
HuangMPangXLetourneauRBoucherWTheoharidesTC. Acute stress induces cardiac mast cell activation and histamine release, effects that are increased in Apolipoprotein E knockout mice. Cardiovasc Res (2002) 55(1):150–60.10.1016/S0008-6363(02)00336-X
140
MeersonFUstinovaE. Effect of long-term and short-term stress actions on the heart resistance to anoxia. Bulleten Eksperimentalnoyi Biologii i Meditziny (1983) 1:21–3.
141
Kiecolt-GlaserJKDuraJRSpeicherCETraskOJGlaserR. Spousal caregivers of dementia victims: longitudinal changes in immunity and health. Psychosom Med (1991) 53(4):345–62.10.1097/00006842-199107000-00001
142
Vrshek-SchallhornSStroudCBMinekaSHammenCZinbargREWolitzky-TaylorKet alChronic and episodic interpersonal stress as statistically unique predictors of depression in two samples of emerging adults. J Abnorm Psychol (2015) 124(4):918–32.10.1037/abn0000088
143
DaveyASharmaPDaveySShuklaASrivastavaKVyasS. Are the adverse psychiatric outcomes reflection of occupational stress among nurses: an exploratory study. Asian J Med Sci (2015) 7(1):96–100.10.3126/ajms.v7i1.12869
144
SeibCWhitesideEHumphreysJLeeKThomasPChopinLet alA longitudinal study of the impact of chronic psychological stress on health-related quality of life and clinical biomarkers: protocol for the Australian Healthy Aging of Women Study. BMC Public Health (2014) 14:9.10.1186/1471-2458-14-9
145
SansSKestelootHKromhoutD. The burden of cardiovascular diseases mortality in Europe. Task Force of the European Society of Cardiology on Cardiovascular Mortality and Morbidity Statistics in Europe. Eur Heart J (1997) 18(8):1231–48.10.1093/oxfordjournals.eurheartj.a015434
146
RosengrenASubramanianSVIslamSChowCKAvezumAKazmiKet alEducation and risk for acute myocardial infarction in 52 high, middle and low-income countries: INTERHEART case-control study. Heart (2009) 95(24):2014–22.10.1136/hrt.2009.182436
147
FerrieJEKivimakiMShipleyMJDavey SmithGVirtanenM. Job insecurity and incident coronary heart disease: the Whitehall II prospective cohort study. Atherosclerosis (2013) 227(1):178–81.10.1016/j.atherosclerosis.2012.12.027
148
NetterstromBKristensenTSJensenGSchnorP. Is the demand-control model still a useful tool to assess work-related psychosocial risk for ischemic heart disease? Results from 14 year follow up in the Copenhagen City Heart study. Int J Occup Med Environ Health (2010) 23(3):217–24.10.2478/v10001-010-0031-6
149
TorenKSchiolerLGiangWKNovakMSoderbergMRosengrenA. A longitudinal general population-based study of job strain and risk for coronary heart disease and stroke in Swedish men. BMJ Open (2014) 4(3):e004355.10.1136/bmjopen-2013-004355
150
KivimakiMFerrieJEBrunnerEHeadJShipleyMJVahteraJet alJustice at work and reduced risk of coronary heart disease among employees: the Whitehall II study. Arch Intern Med (2005) 165(19):2245–51.10.1001/archinte.165.19.2245
151
KivimakiMJokelaMNybergSTSingh-ManouxAFranssonEIAlfredssonLet alLong working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603,838 individuals. Lancet (2015) 386(10005):1739–46.10.1016/S0140-6736(15)60295-1
152
SparenPVageroDShestovDBPlavinskajaSParfenovaNHoptiarVet alLong term mortality after severe starvation during the siege of Leningrad: prospective cohort study. BMJ (2004) 328(7430):11.10.1136/bmj.37942.603970.9A
153
GrippoAJBeltzTGJohnsonAK. Behavioral and cardiovascular changes in the chronic mild stress model of depression. Physiol Behav (2003) 78(4–5):703–10.10.1016/S0031-9384(03)00050-7
154
CarneyRMFreedlandKE. Depression, mortality, and medical morbidity in patients with coronary heart disease. Biol Psychiatry (2003) 54(3):241–7.10.1016/S0006-3223(03)00111-2
155
WulsinLRSingalBM. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom Med (2003) 65(2):201–10.10.1097/01.PSY.0000058371.50240.E3
156
EdmondsonDCohenBE. Posttraumatic stress disorder and cardiovascular disease. Prog Cardiovasc Dis (2013) 55(6):548–56.10.1016/j.pcad.2013.03.004
157
EdmondsonDKronishIMShafferJAFalzonLBurgMM. Posttraumatic stress disorder and risk for coronary heart disease: a meta-analytic review. Am Heart J (2013) 166(5):806–14.10.1016/j.ahj.2013.07.031
158
VaccarinoVGoldbergJRooksCShahAJVeledarEFaberTLet alPost-traumatic stress disorder and incidence of coronary heart disease: a twin study. J Am Coll Cardiol (2013) 62(11):970–8.10.1016/j.jacc.2013.04.085
159
KaplanJRManuckSBClarksonTBLussoFMTaubDMMillerEW. Social stress and atherosclerosis in normocholesterolemic monkeys. Science (1983) 220(4598):733–5.10.1126/science.6836311
160
RatcliffeHLLuginbuhlHSchnarrWRChackoK. Coronary arteriosclerosis in swine: evidence of a relation to behavior. J Comp Physiol Psychol (1969) 68(3):385–92.10.1037/h0027520
161
LiangBVerrierRLMelmanJLownB. Correlation between circulating catecholamine levels and ventricular vulnerability during psychological stress in conscious dogs. Exp Biol Med (1979) 161(3):266–9.10.3181/00379727-161-40533
162
RosenfeldJRosenMRHoffmanBF. Pharmacologic and behavioral effects on arrhythmias that immediately follow abrupt coronary occlusion: a canine model of sudden coronary death. Am J Cardiol (1978) 41(6):1075–82.10.1016/0002-9149(78)90860-3
163
GrippoAJJohnsonAK. Biological mechanisms in the relationship between depression and heart disease. Neurosci Biobehav Rev (2002) 26(8):941–62.10.1016/S0149-7634(03)00003-4
164
GrippoAJFrancisJBeltzTGFelderRBJohnsonAK. Neuroendocrine and cytokine profile of chronic mild stress-induced anhedonia. Physiol Behav (2005) 84(5):697–706.10.1016/j.physbeh.2005.02.011
165
GrippoAJBeltzTGWeissRMJohnsonAK. The effects of chronic fluoxetine treatment on chronic mild stress-induced cardiovascular changes and anhedonia. Biol Psychiatry (2006) 59(4):309–16.10.1016/j.biopsych.2005.07.010
166
SgoifoACarnevaliLGrippoAJ. The socially stressed heart. Insights from studies in rodents. Neurosci Biobehav Rev (2014) 39:51–60.10.1016/j.neubiorev.2013.12.005
167
WoodSK. Cardiac autonomic imbalance by social stress in rodents: understanding putative biomarkers. Front Psychol (2014) 5:950.10.3389/fpsyg.2014.00950
168
MancardiDTullioFCrisafulliARastaldoRFolinoAPennaCet alOmega 3 has a beneficial effect on ischemia/reperfusion injury, but cannot reverse the effect of stressful forced exercise. Nutr Metab Cardiovasc Dis (2009) 19(1):20–6.10.1016/j.numecd.2008.01.004
169
KolarFJezkovaJBalkovaPBrehJNeckarJNovakFet alRole of oxidative stress in PKC-delta upregulation and cardioprotection induced by chronic intermittent hypoxia. Am J Physiol Heart Circ Physiol (2007) 292(1):H224–30.10.1152/ajpheart.00689.2006
170
NalivaikoE. Animal models of psychogenic cardiovascular disorders: what we can learn from them and what we cannot. Clin Exp Pharmacol Physiol (2011) 38(2):115–25.10.1111/j.1440-1681.2010.05465.x
171
JiaMSmerinSEZhangLXingGLiXBenedekDet alCorticosterone mitigates the stress response in an animal model of PTSD. J Psychiatr Res (2015) 60:29–39.10.1016/j.jpsychires.2014.09.020
172
ChourbajiSZacherCSanchis-SeguraCDormannCVollmayrBGassP. Learned helplessness: validity and reliability of depressive-like states in mice. Brain Res Brain Res Protoc (2005) 16(1–3):70–8.10.1016/j.brainresprot.2005.09.002
173
LiBYangCJYueNLiuYYuJWangYQet alClomipramine reverses hypoalgesia/hypoesthesia and improved depressive-like behaviors induced by inescapable shock in rats. Neurosci Lett (2013) 541:227–32.10.1016/j.neulet.2013.01.055
174
ArmarioAOrtizRBalaschJ. Effect of crowding on some physiological and behavioral variables in adult male rats. Physiol Behav (1984) 32(1):35–7.10.1016/0031-9384(84)90066-0
175
BugajskiJ. Social stress adapts signaling pathways involved in stimulation of the hypothalamic-pituitary-adrenal axis. J Physiol Pharmacol (1999) 50(3):367–79.
176
BugajskiJBoryczJGlodRBugajskiAJ. Crowding stress impairs the pituitary-adrenocortical responsiveness to the vasopressin but not corticotropin-releasing hormone stimulation. Brain Res (1995) 681(1–2):223–8.10.1016/0006-8993(95)00297-4
177
SgoifoAKoolhaasJDe BoerSMussoEStilliDBuwaldaBet alSocial stress, autonomic neural activation, and cardiac activity in rats. Neurosci Biobehav Rev (1999) 23(7):915–23.10.1016/S0149-7634(99)00025-1
178
VicarioMAlonsoCGuilarteMSerraJMartinezCGonzalez-CastroAMet alChronic psychosocial stress induces reversible mitochondrial damage and corticotropin-releasing factor receptor type-1 upregulation in the rat intestine and IBS-like gut dysfunction. Psychoneuroendocrinology (2012) 37(1):65–77.10.1016/j.psyneuen.2011.05.005
179
ZoladzPRFleshnerMDiamondDM. Psychosocial animal model of PTSD produces a long-lasting traumatic memory, an increase in general anxiety and PTSD-like glucocorticoid abnormalities. Psychoneuroendocrinology (2012) 37(9):1531–45.10.1016/j.psyneuen.2012.02.007
180
ZoladzPRFleshnerMDiamondDM. Differential effectiveness of tianeptine, clonidine and amitriptyline in blocking traumatic memory expression, anxiety and hypertension in an animal model of PTSD. Prog Neuropsychopharmacol Biol Psychiatry (2013) 44:1–16.10.1016/j.pnpbp.2013.01.001
181
ZoladzPRParkCRFleshnerMDiamondDM. Psychosocial predator-based animal model of PTSD produces physiological and behavioral sequelae and a traumatic memory four months following stress onset. Physiol Behav (2015) 147:183–92.10.1016/j.physbeh.2015.04.032
182
WilsonCBMcLaughlinLDNairAEbenezerPJDangeRFrancisJ. Inflammation and oxidative stress are elevated in the brain, blood, and adrenal glands during the progression of post-traumatic stress disorder in a predator exposure animal model. PLoS One (2013) 8(10):e76146.10.1371/journal.pone.0076146
183
WilsonCBEbenezerPJMcLaughlinLDFrancisJ. Predator exposure/psychosocial stress animal model of post-traumatic stress disorder modulates neurotransmitters in the rat hippocampus and prefrontal cortex. PLoS One (2014) 9(2):e89104.10.1371/journal.pone.0089104
184
RorabaughBRRossSAGaivinRJPapayRSMcCuneDFSimpsonPCet alAlpha1a- but not alpha1B-adrenergic receptors precondition the ischemic heart by a staurosporine-sensitive, chelerythrine-insensitive mechanism. Cardiovasc Res (2005) 65(2):436–45.10.1016/j.cardiores.2004.10.009
185
BanerjeeALocke-WinterCRogersKBMitchellMBBrewECCairnsCBet alPreconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res (1993) 73(4):656–70.10.1161/01.RES.73.4.656
186
DavelAPKawamotoEMScavoneCVassalloDVRossoniLV. Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation. Br J Pharmacol (2006) 148(5):629–39.10.1038/sj.bjp.0706749
187
KimHKParkWSWardaMParkSYKoEAKimMHet alBeta adrenergic overstimulation impaired vascular contractility via actin-cytoskeleton disorganization in rabbit cerebral artery. PLoS One (2012) 7(8):e43884.10.1371/journal.pone.0043884
188
PyeMPCobbeSM. Mechanisms of ventricular arrhythmias in cardiac failure and hypertrophy. Cardiovasc Res (1992) 26(8):740–50.10.1093/cvr/26.8.740
189
LochnerAGenadeSTrompEPodzuweitTMoolmanJA. Ischemic preconditioning and the beta-adrenergic signal transduction pathway. Circulation (1999) 100(9):958–66.10.1161/01.CIR.100.9.958
190
SuematsuYAnttilaVTakamotoSdel NidoP. Cardioprotection afforded by ischemic preconditioning interferes with chronic beta-blocker treatment. Scand Cardiovasc J (2004) 38(5):293–9.10.1080/14017430410021507
Summary
Keywords
stress, cardiovascular, ischemia, anxiety, PTSD, rodent
Citation
Eisenmann ED, Rorabaugh BR and Zoladz PR (2016) Acute Stress Decreases but Chronic Stress Increases Myocardial Sensitivity to Ischemic Injury in Rodents. Front. Psychiatry 7:71. doi: 10.3389/fpsyt.2016.00071
Received
25 January 2016
Accepted
08 April 2016
Published
25 April 2016
Volume
7 - 2016
Edited by
Stefan Oskar Reber, University of Ulm, Germany
Reviewed by
Tobias Opthof, Academic Medical Center, Netherlands; Angela J. Grippo, Northern Illinois University, USA
Updates
Copyright
© 2016 Eisenmann, Rorabaugh and Zoladz.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Phillip R. Zoladz, p-zoladz@onu.edu
Specialty section: This article was submitted to Affective Disorders and Psychosomatic Research, a section of the journal Frontiers in Psychiatry
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.