Volume 28, Issue 1 (Winter 2021)                   Intern Med Today 2021, 28(1): 38-53 | Back to browse issues page

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Nequee F. Effectiveness of Stress Inoculation Training on Heart Rate Variability, Salivary Cortisol, Anxiety, Stress, and Depression after Coronary Artery Bypass Graft Surgery. Intern Med Today 2021; 28 (1) :38-53
URL: http://imtj.gmu.ac.ir/article-1-3671-en.html
Department of Psychology, Mahallat Branch, Payam Noor University, Mahallat, Iran. , nequee@yahoo.com
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Heart disease is one of the most common diseases in the world and is still the leading cause of death in various countries [1]. A large number of coronary heart disease cases that do not respond to drug therapy require Coronary Artery Bypass Graft (CABG) surgery [2]. In Iran, CABG surgery has been conducted in 60% of heart disease cases [3]. Numerous studies indicate an increase in psychological problems, especially depression and anxiety among patients as clinical outcomes [1, 4]. These psychological disorders are common in patients with heart disease, especially those received CABG surgery, with a prevalence rate of 25-55% [7]. Depression is three times more common in patients with coronary heart disease than in normal people, as it is a risk factor for cardiovascular diseases and can increases the prevalence and mortality rates in patients [8]. Recent meta-analysis studies have shown that depressive symptoms are associated with an increased risk of cardiac event in these patients; the presence of depressive symptoms after myocardial infarction is associated with an increased risk of subsequent heart attack and relative risk [1]. The coronary heart disease death rate increases in patients with increasing depression [6]. The studies show that depression, and especially severe depression, predicts the worsening of prognosis in patients with coronary heart disease. 
Anxiety is another most common psychological disorder in patients with coronary heart disease [2]. It includes feelings of insecurity, helplessness and arousal in these patients, and is usually defined as a diffuse and vague sense of fear [8]. If it left untreated, it can increase the likelihood of next cardiac event [9]. Its prevalence is 60% higher in heart disease patients than in normal people. In a meta-analysis study, anxiety was reported to be an independent risk factor for heart attack [9]. In various studies, the level of anxiety after CABG surgery is estimated to be 24.7%-40% and in Iran, about 65% of patients experience it after surgical and medical interventions [10]. Anxiety is known as a disturbing factor in the treatment process [11] and the patients undergoing CABG surgery can experience anxiety for various reasons such as severe chest pain, fatigue, and fear of death or disability, which can lead to increased postoperative pain [12], increased need for the use of painkillers, delayed postoperative recovery, rapid breathing with decreasing depth, incidence of pulmonary complications, decreased postoperative activity, increased thrombosis and intestinal dysfunction, increased risk of infection, and decreased immune response [4]. 
Studies have shown that physical and mental stress is a factor in the release of various glucocorticoid hormones by activating the Hypothalamic-Pituitary-Adrenal (HPA) axis and catecholamines (through the sympathetic nervous system) [10]. Elevated cortisol levels indicates to be in a stressful situation and are associated with increased anxiety and especially severe clinical depression [13]. Therefore, reducing these psychological problems can improve a person’s health by adjusting the HPA axis [12]. Stress, whether physical or mental, causes changes in heart function and the secretion of stress hormones [15]. Increased heart rate and hormonal changes can have dangerous physiological effects on the nervous and cardiovascular systems [14]. These psychological problems can cause heart rate instability in patients with heart disease and changes in the degree of psycho-physiological coordination of Heart Rate Variability (HRV) [13]. The psycho-physiological coordination of HRV is a non-invasive, practical and reproducible indicator of the function and activity of the autonomic nervous system, and indicates a time interval between consecutive heartbeats in response to environmental changes. It is associated with the risk of cardiovascular disease [13]. Emotional imbalance in patients with heart disease is seen as increased baroreflex sensitivity and decreased HRV. Low psycho-physiological coordination of HRV doubles the risk of mortality in these patients [12]. Depressed patients with or without coronary heart disease show decreased psychological coordination of HRV. This decrease seems to be related to the severity of depression. Patients with both coronary heart disease and depression show a greater reduction in HRV than patients with only one of these two diseases [13].
Emotional regulation by cognitive-behavioral approaches is an effective method for increasing the psycho-physiological coordination of HRV and decreasing salivary cortisol [17]. One of the most effective cognitive-behavioral approaches for this purpose is Stress Inoculation Training (SIT) developed by Meichenbaum, which combines some of the best elements of behavioral and cognitive therapy [18]. The basic principle in SIT is to pay attention to the process of thinking, feeling, and behavior, and considers the impact on others as a basic prerequisite for changing a behavior and directly emphasizes the thoughts, feelings, perception and daily life of people [20]. Meichenbaum has proposed three stages for SIT: (a) the conceptualization stage, when the therapist talks with the patient about stress [19], (b) the skill acquisition and rehearsal stage, where the therapist works on cognitive and behavioral skills of patients using different methods such new information, cognitive reconstruction, changing negative self-talk to positive self-talk, behavioral effort for relaxation, assertiveness, and self-confidence to deal with stressful situations [21], and (c) Application and follow-through stage, where the patients learn to apply stress reduction techniques to practice the skills learned in real life [22]. 
Strickland et al. in a study on the effectiveness of SIT on the quality of life in patients with acute coronary syndrome, showed that the SIT improves the quality of life of these patients by the reduction of anxiety, depression and perceived stress and increasing coping strategies to reduce systolic blood pressure [23, 25]. In this therapeutic approach, patients are encouraged to assess the relationship between their negative spontaneous thoughts and feelings of depression, and use behaviors resulted from negative spontaneous thoughts as a criterion for assessing the validity of these thoughts and correct their self-talk [19]. The difference between this study and previous studies was in the number of training sessions, the use of a 3-month follow-up and assessment of HPA axis activity using saliva cortisol and HRV.
Materials and Methods 

This is a quasi-experimental study with pretest/posttest /follow-up design. The study population consists of patients with CABG surgery referred to the Cardiac Rehab center of Tehran Heart Hospital in Iran. Sample size based on p, experimental group, control group, variable response variance, significance level and test power, 25 patients were randomly selected and placed in the experimental group (immunization against stress) and the control group. Inclusion criteria were: Having a history of CABG surgery, age <70 years, literacy, no primary or secondary cognitive impairment based on patients’ medical records, and ability to communicate. Exclusion criteria were: unwillingness to continue participation, absence or not attending the training sessions.
Saliva cortisol test was used to assess cortisol levels in saliva. For collecting saliva samples, the spitting method was used [25]. Samples were immediately transferred to the laboratory after collecting. Given that cortisol has a rhythm that is affected by sleep, sampling time was the same at all stages (pretest and posttest phases). In this regard, the effect of circadian rhythm on hormonal secretion was controlled. The saliva samples were kept frozen at -23 ° C until performing test. To measure salivary cortisol levels, a cortisol saliva ELISA kit (52611-RE, IBL Company, Germany) with a sensitivity of 0.03 micrograms per deciliter were used.
The 21-item Depression, Anxiety and Stress Scale (DASS-21) was used to measure depression, anxiety and stress of patients. The acceptable validity and reliability of this questionnaire on Iranian samples have been already reported [26]. Besharat (2005) reported the Cronbach’s alpha coefficients of Persian DASS-21 as 0.87 for depression subscale, 0.85 for anxiety subscale, 0.89 for stress subscale, and 0.91 for the overall scale in general population, and 0.89, 0.91, 0.87, and 0.93 in clinical population, respectively. They assessed concurrent validity, convergent validity and diagnostic validity of Persian DASS-21 in comparison with the Beck Depression Scale, Beck Anxiety Scale, Positive and Negative Affective Schedule, and Depression Scale, Anxiety and Stress (DASS-21) in clinical and general populations. Their results showed a positive and significant correlation between the scores of subjects in the subscales of depression, anxiety and stress with the scores of mentioned questionnaires. There is a significant negative correlation between negative emotions (0.44-0.58, P<0.0001) and positive emotions (0.41-0.58, P<0.001). These results confirm the concurrent, convergent and diagnostic validity of the Persian DASS-21.
For assessment of psycho-physiological coordination of HRV, the first step was the R-wave detection in the ECG signals. After determining the exact location of R waves, the signal of HRV was obtained by calculating the time intervals between two consecutive R waves. To evaluate the function of the autonomic nervous system, the number of fluctuations in RR interval was analyzed by an electrocardiogram [2]. According to the frequency parameters of the HRV, High Frequency (HF) waves (0.5-0.15 Hz) mainly reflect the activity of the parasympathetic nerve, Low Frequency (LF) waves (0.04-0.15 Hz) mainly reflect the activity of sympathetic nerve as well as regression in parasympathetic nerve activity, and Total Power (TP) waves (0.04-0.5 Hz) indicate the general activity of the autonomic nerves. Compared to other clinical cardiac reflex tests, this method can assess the function of the autonomic nervous system better with more sensitivity [27]. To measure HRV, the Fast Fourier Transform (FFT) frequency axis was used to detect changes at different frequencies. Each participant was asked to lie down for 15 minutes to monitor your heartbeat in a quiet and dimly lit room. The resting heart rate was then monitored by a Holter monitor for 10 minutes. Then, the spectral analysis was performed on spontaneous changes in heart rate and the results were used to calculate the frequency range of HRV parameters in software. Patients with non-sinus rhythm (having atrial fibrillation) were excluded from the study, because the HRV in these individuals could not be measured.
The SIT was presented at 10 sessions based on Meichenbaum’s approach. In these sessions, we described the role of SIT in controlling stress and reducing relapse and disease progression and discussed about cognitive errors, challenges with negative stresses, negative thoughts, familiarity with internal dialogue , the role of negative internal dialogue in stress creation, use of positive internal dialogues instead of negative internal dialogue, the use of attention techniques, expressing the importance and necessity of problem solving, and training problem solving skills. In the final session, we reviewed the skills taught in previous sessions. In the sessions, the barriers and difficulties in performing skills in everyday life were emphasized. At the end, DASS-21 was completed again by the patients, their HRV was monitored, and salivary cortisol samples were collected.
Data analysis
Data were analyzed using Multivariate ANCOVA.
Thirty patients participated in this study, of whom 66.81% were male and 33.19% female. Most of them were at the age range of 60-69 years (45.7%) and minority of them were at the age range of 40-49 years (15.8%). Moreover, 89.3% of them were married and 92.8% were unemployed. In Table 2, the mean level of salivary cortisol, HRV, anxiety, stress and depression at pretest, posttest, and follow-up phases in both groups are presented.

As can be seen, there was no significant difference in demographic and clinical variables at baseline between the two groups, but the post-test and follow-up scores of HRV, Cortisol, depression, stress and anxiety were significantly different. The results of box’s M test showed that the significance level was 0.1, indicating that the homogeneity of the variance-covariance matrix was ​​observed in the study groups (p> 0.05). The results of Levene’s test for the post-test scores of dependent variables reported the equality of variances (p>0.05). The results of Wilk’s lambda test showed a significant difference between the two groups in at least one of the variables (F=0.640). In assessing the effect of group on dependent variables, after controlling the effects of covariates (pre-test scores), results showed that six dependent variables of stress, anxiety, depression, HRV and cortisol level were significantly affected by the group cognitive-behavioral therapy based on SIT method (F=2.056, P=0.001, η2=0.702). The multivariate analysis of covariance was conducted to examine whether each dependent variable is affected by the independent variable. According to its results presented in Table 4, there was a significant difference between the two groups in terms of study variables (P<0.05).

The effect of SIT on stress (F=202.640, ms=110.1064, η2=0.882); Anxiety (F=807.204, ms=295.695, η2=0.833); Depression (F=924/61, ms=130/762, η2=0.696); HRV (F=2.258, ms=048/0, η2=0.077); Cortisol (F=72.747, ms=0.317, η2=0.728) was significant. The SIT had the greatest effect on stress (η2=0.794), anxiety (η2=0.833) and cortisol level (η2=0.181).
As can be seen from Table 4, results of pairwise comparison using Bonferroni test showed that there were significant differences between the two groups in psychological (stress, anxiety, depression) and physiological (HRV, cortisol level) variables (P<0.001). In other words, the SIT had a significant effect on reducing stress, anxiety, depression, cortisol and increasing HRV and this effectiveness was statistically significant.
The results of this study showed that, after a 10 sessions of intervention by the SIT method, there was a significant difference between the intervention and control groups in salivary cortisol level, HRV, anxiety, stress and depression. Regarding the effect of SIT on depression in the intervention group, our finding is consistent with the results of Liou et al. [28]. Regarding the effect of SIT on the HRV, our result is consistent with the findings of Nishith et al. [29].
Reduction of patients’ depression by the skills they learned, can help them deal with chronic heart disease in a new way and able to test their previous beliefs in stressful situations. These beliefs can increase a person’s self-efficacy. When patients feel that they can control their living environment after surgery, they can make environmental changes and review successful experiences which can increase their ability in managing stressful situations. This positive inner perception of patients can help them manage their grief. By the SIT method, the patient changes from a person who need comfort and relaxation to have mental and physical health to a person who achieves these goals. It will be born and generalized to other life situations  And this positive inner perception of people manages the emotion of grief following the feeling of losing health. In this treatment, the mental path of the patients changes from someone who must be provided with comfort and relaxation in order to be able to enjoy a calm mental and physical health, to a person who also achieves these goals. On the other hand, participating in a group therapy cause patients to experience the positive results of social relationships; by not seeing themselves as being alone, and with the help of others, they find out more about the issues discussed in the group, including the disease and its perception, and can benefit from the positive results of the intervention sessions in real life by using the learning skills to address problems in everyday life.
The effect of SIT on increasing the HRV study was based on sympathetic and parasympathetic nerve activities. Relaxation exercises in the training program could increase the balance of sympathetic and parasympathetic nerves activities which affected the respiration and heart rates and reduced tachycardia. These relaxation exercises could suppress sympathetic activity and led to vagal stimulation and increased parasympathetic activity. The main mechanism of these changes is the presence of pressure receptors on the arterial wall, which stimulates the vagus and reduces sympathetic activity. These receptors cause the heart rate to return to normal rate through parasympathetic and sympathetic stimulations. Respiration rate is also one of the main and influential factors that affect the functioning of the autonomic nervous system in various organs, such as the heart. Heart rate usually increases when inhaling and decreases when exhaling. The main effect of respiration rate is realized through vagal activity. When a person experiences a sense of muscle relaxation, vagal activity increases which, in turn, reduces respiration and heart rates, and increases psychological coordination of HRV. A deep or longer relaxation has a better effect on this coordination. Therefore, the SIT reduces the heart rate and increase HRV by affecting the respiratory rate. According to the results, both study groups were able to increase the variability of HRV heart rate in the post-test phase, but there was no significant difference between them (P<0.05).
The SIT can reduce anxiety, stress and depression and severe complications of heart disease. Interventions based on SIT are recommended for patients with heart disease. In this study, participants were the patients who had CBAG surgery which limits the generalizability of the findings to all patients with heart disease. In future studies, the SIT should be presented separately for patients with different types of heart disease and its effectiveness be compared between different groups. Moreover, the study of variables such as personality traits, self-efficacy and social support in assessing the effect of SIT is recommended. 

Ethical Considerations
Compliance with ethical guidelines

An ethical approval was obtained from Payame Noor University (Code: IR.PNU.REC.1398.001). 

This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors.

Authors' contributions
The authors had equal contribution to the manuscript.

Conflicts of interest
The authors declare no conflict of interest

The authors would like to thank the staff of cardiac research center in Tehran and all patients for their cooperation in this research. 

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Type of Study: Original | Subject: Mental Health
Received: 2021/02/26 | Accepted: 2021/07/19 | Published: 2022/01/1

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