Introduction

Mental stress-induced myocardial ischaemia (MSIMI) is defined as an imbalance between myocardial oxygen supply and demand during mental or psychological stress. The data demonstrate that mental stress triggers transient myocardial ischaemia in 30–70% of patients with pre-existing coronary artery disease (CAD) [1,2,3]. To date, there are no guidelines on MSIMI, and numerous studies have found a higher prevalence and likelihood of MSIMI in patients with depression/anxiety. [4, 5]. The prevalence of MSIMI in patients with depression/anxiety and CAD was 22.08 times higher than for patients without depression/anxiety [4]. In addition, studies have also shown that a 1-point increase in the anxiety score is associated with a 1.22-fold increase in the likelihood of MSIMI, and a 5-point increase in the depression score is associated with a roughly twofold increase in the likelihood of MSIMI [4, 5].

The Seattle Angina Questionnaire (SAQ) is specific for CAD and has been widely accepted as a means of quantifying the outcome of CAD treatment on patients’ angina and QoL in trials [6]. The SAQ measures five subscales related to CAD, namely, physical limitations, angina frequency, angina stability, treatment satisfaction, and QoL. Among the MSIMI trials, only the angina-frequency subscale has been found to be related to MSIMI in women with stable CAD [7] and in post-myocardial infarction patients [8]. However, a comprehensive assessment of the five SAQ subscales, especially QoL and MSIMI, is limited.

Therefore, this study was designed to examine the association between SAQ and MSIMI in high-risk patients with depression/anxiety prior to revascularization and whose CAD stabilized after at least 1 month of revascularization. In addition, the association between MSIMI and the benefit or drawback of CAD revascularization assessed by SAQ was evaluated.

Methods

Study sample

In the study of CAD with a high risk of MSIMI patients, 1845 patients with coronary angiography-confirmed CAD who received coronary revascularization treatment, including percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), were screened between Dec 2018 and Dec 2019. The mental health status of all patients was assessed using the nine-item Patient Health Questionnaire-9 (PHQ-9) and the seven-item Generalized Anxiety Disorder-7 (GAD-7) severity measure. Those with screened depression/anxiety (PHQ-9 ≥ 5 and/or GAD-7 ≥ 5) were enrolled in this study. The study protocol was approved by the Medical Ethics Committee of Beijing Anzhen Hospital (NO. 2019001), and all participants provided informed consent prior to inclusion in this study.

Mental stress test

Mental stress was induced by the Stroop Colour and Word Test (SCWT), which was employed to assess the ability to inhibit cognitive interference. The SCWT has been well accepted for assessing patients with CAD and has been shown to exhibit good reproducibility and execution [9, 10]. A standardized computer program was used to test the participants. Four words were displayed on the computer screen (i.e., “RED,” “BLUE,” “GREEN,” AND “YELLOW”), and corresponding buttons were labelled with one of four letters (i.e., “J,” “K,” “L,” and “I”). The computer randomly assigned the four colours to these four words, and only one word appeared at a time. The participant was instructed to match the word with the corresponding button without being distracted by the colour. For example, for the word “RED” presented in yellow, “J” should be selected rather than “I”. If the answer was wrong, the word “ERROR” appeared on the screen, and if the participant responded not quickly enough, the screen displayed the words “RESPOND FASTER”. During the test, an auditory stimulus was initiated by the examiners. The accuracy, response time, stimulus presentation velocity, and test duration were recorded by the computer. During the continuum of visual stimuli, a cognitive mechanism was applied to direct attention. The procedure included the following: (1) the participant was informed about the testing process and underwent a practice test that lasted approximately 1 min and then (2) the participant underwent a timed test. The SCWT lasted approximately 5 min. Non-invasive continuous blood pressure and heart rate measurements were performed every minute. The rate–pressure product (RPP) was calculated as systolic blood pressure (SBP) × heart rate (HR). The maximum values of SBP and HR during mental stress were selected.

Single photon emission computed tomography (SPECT) myocardial perfusion imaging

Each participant underwent electrocardiographically gated technetium-99 m (99mTc)-sestamibi SPECT imaging 1 month after PCI/CABG. All participants underwent two SPECT scans on two separate days: the first one at rest and the second one after mental stress. The patients received 99mTc-sestamibi at a dose of 20–25 mCi during the rest and stress phases. The SCWT mental stress test lasted approximately 5 min, and 99mTc-sestamibi was intravenously administered 1 min after the test started. Images were acquired using an e-Cam Duet gamma camera (Siemens AG, Erlangen, Germany) 60–90 min after the intravenous administration of 99mTc-sestamibi.

The SPECT images were individually analysed by two experienced readers blinded to patient data. The extent and severity of myocardial ischaemia were assessed using a 17-segment model with Quantitative Gated SPECT software. Tridimensional reconstruction of the left ventricle was performed to assess ventricular function, in addition to the analyses of ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), contractility, and myocardial thickness [10]. Four abnormal SPECT phenomena were considered positive for MISIMI [11, 12], including reversible myocardial perfusion defects, transient ischaemic dilation (TID), reverse redistribution, and EF reduction of ≥ 5% [13]. The mental stress and rest images were analysed using total perfusion deficit (TPD) [14, 15].

Assessment of coronary-related quality of life

The 19-item SAQ questionnaire, which measures five domains related to CAD, was used to assess angina frequency, physical limitations, angina stability, treatment satisfaction, and QoL. The scores ranged from 0 to 100, with higher scores indicating fewer symptoms and a better health status [16]. The participants were evaluated using the SAQ before revascularization and 1 month after revascularization. Significant improvements in each subscale were predefined for physical limitation (≥ 8 points), angina frequency (≥ 20 points), and QoL (≥ 16 points) [17].

Statistical analysis

Continuous variables were reported as the mean ± standard deviation or median (Q1/Q3) when appropriate, and categorical variables were reported as numbers and percentages. Concomitant medication was summarized and compared between the groups at discharge and after 1 month using the χ2 test or Fisher’s exact test, whichever was appropriate. Each domain of the SAQ was evaluated using analysis of covariance before and after revascularization. Continuous variables were compared between groups using independent samples t test or Mann–Whitney-U Test. Within the same group, the differences in SAQ scores before and after revascularization were compared using a paired samples t test. For all other endpoints, a two-sided probability (p) value of 0.05 without correction for multiple testing was considered statistically significant. Logistic regression was used to identify the factors associated with MSIMI. The model was adjusted for coronary risk factors and imbalance factors before revascularization.

Results

Of the 1,845 consecutive patients with CAD who received PCI/CABG, 590 (31.9%) exhibited depression/anxiety, and 205 agreed to undergo the mental stress test. Overall, 105 (51.2%) patients exhibited MSIMI. The enrolment and evaluation process are shown in the flow chart (see Fig. 1).

Fig. 1
figure 1

Flow chart of patient enrolment and the evaluation process

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The mean age of the participants was 59.72 years (standard deviation [SD], 10.1), and 64 (31.2%) of the participants were women. The mental stress test was performed subsequent to an average observation period of 33 days (30/40) after coronary revascularization.

Among 105 patients exhibiting MSIMI, 59 (56.2%) had reversible myocardial perfusion defects, 30 (28.6%) had an EF reduction of ≥ 5%, 27 (25.7%) had TIDs, and 13 (12.4%) had reverse redistribution. Furthermore, 82 patients had only one abnormal phenomenon, 22 patients displayed a combination of two abnormal phenomena, and 1 patient exhibited three abnormal phenomena. The characteristics of the 205 patients before revascularization in the MSIMI and non-MSIMI groups are shown in Table 1. There were no significant differences between the two groups in the demographic risk factors or the angiographic severity of CAD. However, the MSIMI group demonstrated significantly higher PHQ-9 scores and longer disease duration while the non-MSIMI group had a higher drinking history percentage.

Table 1 Characteristics of the MSIMI and non-MSIMI groups before revascularization
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Before mental stress, at rest, the left ventricle EDV and ESV were lower in the MSIMI group than in the non-MSIMI group (79.2 ± 30.1 vs. 92.7 ± 44.1 and 30.1 ± 21.7 vs. 40.4 ± 34.8, respectively, P < 0.05). Furthermore, EF was higher in the MSIMI group than in the non-MSIMI group (64.8 ± 12.8 vs. 60.0 ± 12.4, P < 0.01). On the day of the mental stress screening, there were no significant differences in EDV, ESV, or EF between the two groups, except for the higher proportion of stress TPD in the MSIMI group. Moreover, non-invasively measured SBP, DBP, HR, and RPP were similar in the two groups both at rest and during the mental stress test (see Table 2). None of the patients developed chest pain during the test.

Table 2 Differences in the indices between the non-MSIMI and MSIMI groups before and after mental stress
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The five subscales measured using the SAQ questionnaire were similar between the non-MSIMI and MSIMI groups before revascularization. The only exception was physical limitations, which were significantly lower in the MSIMI group than in the non-MSIMI group (52.4 ± 20.2 vs. 58.7 ± 17.6, P = 0.025, see Table 3). At 1 month after coronary revascularization, all subscales were significantly improved in both groups (P < 0.001), except for the QoL subscale in the MSIMI group. Although the QoL improved significantly in the non-MSIMI group after coronary revascularization, the score was numerically but not statistically lower in the MSIMI group (see Fig. 2). Moreover, the QoL score was lower in the MSIMI group than in the non-MSIMI group after revascularization (51.5 ± 22.4 vs. 58.4 ± 22.8, P = 0.031).

Table 3 Five domains of the SAQ prior to treatment and 1 month after coronary revascularization in the non-MSIMI and MSIMI groups
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Fig. 2
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Change in the SAQ results of the non-MSIMI and MSIMI groups before and after coronary revascularization (*P < 0.05)

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Table 4 shows the improvements in the five domains of the SAQ questionnaire. The absolute values of the improvements in physical limitations, angina frequency, angina stability, and treatment satisfaction were similar between the two groups. However, the improvement in QoL showed a significant difference between the two groups (13.1 ± 29.9 vs. − 0.2 ± 32.7, P = 0.005, see Fig. 3). More patients in the MSIMI group presented a significant improvement in the physical limitation subscale (87.9% vs. 76.3%, P = 0.041), and fewer patients in the MSIMI group showed a significant improvement in the QoL subscale (31.9% vs. 50.5%, P = 0.010). Overall, QoL showed a consistently deteriorating trend in the MSIMI group but not in the non-MSIMI group.

Table 4 Association between the improvements in SAQ and MSIMI
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Fig. 3
figure 3

Comparisons of the SAQ improvements between the MSIMI and non-MSIMI groups after coronary revascularization

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In the cohort that had CAD associated with depression/anxiety, the probability of MSIMI after 1 month of coronary revascularization was approximately two times higher in patients with a deterioration in QoL than in those with an improvement in QoL (unadjusted odds ratio [OR]: 2.019, 95% confidence interval [CI] 1.122–3.634; adjusted OR: 1.968, 95% CI 1.083–3.578). Similarly, an improved QoL score of < 16 was associated with a twofold increase in the probability of MSIMI when compared with a score of ≥ 16 (unadjusted OR: 2.184, 95% CI 1.199–3.979; adjusted OR: 2.105, 95% CI: 1.145–3.873) (see Table 5). Furthermore, a score of < 8 on the improved physical limitation subscale was associated with a 55.6% lower probability of MSIMI when compared with a score of ≥ 8 (unadjusted OR: 0.444, 95% CI 0.201–0.979); however, after adjusting for the factors before revascularization, the association with MSIMI did not exhibit statistical significance. In addition, although the decrease in angina frequency had no association with MSIMI, after adjustment, it was associated with a 2.336 times higher probability of MSIMI (adjusted OR: 2.336, 95% CI 1.029–5.301). For the other two subscales, namely, angina stability and treatment satisfaction, the association between deterioration or no significant improvement and MSIMI had no statistical significance.

Table 5 Association between the deterioration or no significant improvement in the SAQ subscales and MSIMI
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Discussion

Among the group with a high risk of MSIMI, i.e., CAD with the comorbidity of depression/anxiety, coronary revascularization significantly improved physical limitations, angina frequency, angina stability, and treatment satisfaction but not QoL. The deterioration in QoL 1 month after coronary revascularization was associated with a two-fold increase in the risk of MSIMI. These findings were independent of traditional CAD risk factors and psychological factors.

Coronary revascularization, including PCI and CABG, has been proven to improve CAD-related SAQ scores in multiple populations. Our findings, except for QoL, are consistent with this observation. Among patients with stable CAD in the COURAGE study [18], SAQ was used to dynamically assess the QoL after PCI or optimal medical treatment (OMT). The greatest improvements were seen in the first 3 months, especially in the three subscales of physical limitations, angina frequency, and QoL. Among the patients with chronic coronary total occlusion lesions in the EUROCTO study [17], a greater improvement in the SAQ subscales was observed with PCI than with OMT for angina frequency and QoL. In a large sample of 3392 patients with CAD, coronary revascularization, regardless of the approach being PCI or CABG, was consistently associated with a significantly higher QoL, as assessed with SAQ at the one-year follow-up, when compared with other medical therapies [19]. In our study cohort of patients with CAD and depression/anxiety, the QoL improved in the non-MSIMI group but deteriorated in the MSIMI group 1 month after PCI or CABG. These findings indicate that MSIMI may weaken the beneficial effect of coronary revascularization on QoL.

In the MSIMI field, only two studies have thus far employed the SAQ to evaluate the relationship between CAD and MSIMI. In 950 patients with stable CAD, the angina frequency subscale of the SAQ was used to assess the probability of MSIMI. Overall, 338 individuals (37%) reported angina. It was found that only women who reported angina had MSIMI [7]. In our study, 47.3% of all patients reported angina, which is higher than that observed in the abovementioned study, but the decrease in angina frequency had only a weak association with MSIMI. This phenomenon could probably be attributed to the differences in the enrolment of participants. In our study, we considered depression/anxiety to be a high-risk factor for MSIMI that would interfere with the results [4, 20, 21]. Therefore, we enrolled patients with depression/anxiety. Previous studies have recorded that patients with depression who underwent revascularization demonstrated a lower improvement in angina frequency than those without depressive symptoms [22]. Consistent with our findings, another study involving 98 post-myocardial infarction patients found that the angina frequency score was positively associated with MSIMI after adjusting for depressive and anxiety symptoms [8]. However, neither study comprehensively evaluated the five subscales of the SAQ. To date, there have been no studies on the relationship between SAQ QoL and MSIMI.

The SAQ scores have been reported to be independently associated with 1-year cardiovascular events among patients with CAD and predict 1-year mortality and cardiac rehospitalizations [23, 24]. The deterioration in QoL might be related to many factors. Depression may lead to a decline in QoL [25]. In addition, depressive symptoms may aggravate the perception of chest pain and result in a worse QoL [22, 26]. Although cognitive behavioural therapy [22] or slow breathing therapy [27] appear to have at least modest benefits in improving QoL, studies examining antidepressant therapies have been inconclusive.

The main strength of our study is the selection of patients with a high risk for MSIMI. Previous studies have shown that depression/anxiety may be a risk factor for MSIMI [4, 20, 21]. Thus, we selected patients with CAD and reported depression/anxiety as the inclusion criterion to eliminate the influence of emotional factors on the results to the best possible extent. Furthermore, in previous MSIMI studies [7, 8, 28,29,30], CAD has mostly been determined based on medical history or self-reporting. However, all participants in our study were confirmed to have CAD via coronary angiography, which is more accurate than the methods used in previous studies. Moreover, considering that endothelial function and coronary microvascular disorders are possible mechanisms of MSIMI [31], except for myocardial perfusion defects, we selected TID, reverse redistribution, and EF reduction of ≥ 5%, which reflected microvascular disorders [11]. Additionally, we specifically evaluated the relationship between MSIMI and ischaemia-related vessels by analysing coronary angiography and SPECT images.

One of the key limitations of our study was the short follow-up period. The average follow-up time was only 33 days. In future research, we plan to follow up and obtain SAQ results at 3 months, 6 months, and 12 months to dynamically evaluate the association with MSIMI. In addition, we did not include the effects of MSIMI and major adverse cardiovascular events. In the future, we intend to follow-up on the events using repeat coronary angiography and psychological stress tests at 12 months.

Conclusion

To the best of our knowledge, this is the first study demonstrating that deterioration in CAD-related QoL is associated with an increased likelihood of MSIMI among patients with CAD and depression/anxiety. Our results highlight the relationship between QoL and the likelihood of MSIMI.