Clin Res Cardiol DOI 10.1007/s00392-014-0782-3
ORIGINAL PAPER
Investigating the role of acute mental stress on endothelial dysfunction: a systematic review and meta-analysis Yi-Tao Xue • Qi-wen Tan • Ping Li • Shan-fang Mou • Shu-juan Liu • Yue Bao Hua-chen Jiao • Wen-Ge Su
•
Received: 10 July 2014 / Accepted: 21 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Chronic stress is a known risk factor for both endothelial dysfunction and cardiovascular disease (CVD), but less is known of how acute mental stress affects the vasculature. In this systematic review and meta-analysis, we analyzed the impact of acute mental stress on flowmediated dilation (FMD), an indicator of endothelial function. We searched the Medline, Cochrane, EMBASE, and ISI Web of Knowledge databases through May 2014, to identify publications in English-language journals. The primary outcome was the change in FMD from baseline to the time of measurement. We also assessed the risk of bias and the heterogeneity of included studies. Our search identified eight prospective studies, which displayed significant heterogeneity. Four studies measured FMD while the subject was performing the task; six measured FMD after the task had been completed. The total number of participants was 164. The pooled results indicate that FMD did not change significantly while the task was being performed (pooled difference in means: -0.853; 95 % confidence interval (CI), -3.926/2.220; P = 0.586); however, FMD measured after the task was completed was significantly less than baseline (pooled difference in means: -2.450; 95 %CI, -3.925/-0.975; P = 0.001). In conclusions, our findings provide evidence that an acute stressful
Y.-T. Xue (&) Department of Cardiology, Shandong University School of Medicine Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 42 West Wenhua Road, Jinan 250011, Shandong Province, China e-mail:
[email protected] Q. Tan P. Li S. Mou S. Liu Y. Bao H. Jiao W.-G. Su Department of Cardiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, Shandong Province, China
experience has a delayed, negative impact on the function of the endothelium. Repeated exposure to short-term stress may lead to permanent injury of the vasculature. Therefore, assessment of patients’ exposure to both repeated acute mental stress and chronic stress may be useful in determining their risk of developing CVD. Keywords Mental stress Endothelial dysfunction Cardiovascular disease Flow-mediated dilation Meta-analysis Systematic review
Introduction Cardiovascular disease is currently one of the leading causes of death in most regions of the world [1]. In the Unites States, one of every three deaths, or approximately, one death every 40 s, was due to CVD in 2010 [2], whereas in China, one person died from CVD every 10 s in 2012 [3]. The number of deaths from CVD was greater for those aged 60–69 years than those aged 70 years or older [4]. Others, such as patients who have HIV or received radiation therapy, are also at increasing risk [5, 6]. Several poorly understood factors including psychological distress and poor sexual health may also influence CVD patients’ survival [7–13]. The high morbidity associated with those surviving with CVD is also very costly. In 2008, CVD resulted in 151 million total global disability-adjusted life years, and the World Economic Forum has estimated that total global cost associated with CVD approached $863 billion (US dollars) in 2010 [14]. Mortality rate due to CVD has decreased in the US and Europe over the past 20 years, but has risen in China and other developing nations [1–3, 15], leading to a net increase in global death rate from 2000 to 2012 [4]. Some
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have attempted to identify biomarkers to detect or predict CVD’s occurrence [16–21]. Rise of CVD stems primarily from the increasing prevalence of highly associated risk factors such as diabetes, obesity, a sedentary lifestyle, and hypertension, in children and adults world-wide [3, 22–24]. Stress has been considered as an independent risk factor for CVD. A few large observational studies have identified correlation between stress and the incidences of myocardial infarction, stroke, and coronary heart disease (CHD) [25– 27]. One possible mechanism by which stress may increase susceptibility to CVD is by affecting the heart rate [28]. Some proposed that impaired vascular endothelial function resulting from decreased nitric oxide (NO) which regulates endothelium’s sensitivity to platelet and monocyte adhesion, can lead to atherogenesis [29, 30]. Stress may also lead to decreased production or increased degradation of NO via changes in the releases of cortisol, epinephrine and/ or norepinephrine [30, 31]. The resulting alterations in endothelial contractility and in vasoprotective activities, including regulation of adhesion and smooth muscle cell proliferation and migration, may facilitate the development of atherosclerosis and increase the risk of CVD [32, 33]. Multiple studies have supported the association of chronic/acute stress with endothelial dysfunction, but results are not consistent [34–38]. Thus, the objective of this review is to provide a comprehensive analysis of studies that have analyzed effects of acute mental stress on arterial flow-mediated dilation (FMD), a well-characterized measurement of endothelial function [39] that quantifies the ability of the vasculature to dilate in response to a stimulus induced by shearing stress resulting from increased blood flow after release of a blood pressure cuff (vascular occlusion).
remaining citations were obtained and examined to determine which would meet all inclusion criteria and none of the exclusion criteria. Reference lists of the included studies were also manually searched to identify additional eligible studies. Two independent reviewers identified eligible studies using the search strategy with a third reviewer consulted if any uncertainty regarding eligibility existed. The protocol for the methods described above has not been registered. Selection criteria A study was considered for inclusion if it met all of the following criteria: (1) examined the relationship between mental stress and endothelial dysfunction; (2) outcomes included FMD; and (3) was a prospective comparative study. A study was excluded if it: (1) used interventions that could affect the level of mental stress; (2) was a letter, comment, editorial, or case report; or (3) was reported in a non-English-language journal. Data extraction The following information was extracted from studies that met the eligibility criteria: name of the first author, year of publication, study design, number of participants in each group, participants’ age and gender, definitions and types of stress intervention, FMD at baseline, during, and after the stress intervention, as well as the elapsed time between the stress intervention and measurement of FMD. The data extraction was performed by two reviewers and any disagreement was resolved by consulting with a third reviewer. Outcome measures
Methods Search strategy The methods adhere to the current practice for conducting systematic reviews of the literature and to PRISMA guidelines [40]. The Medline, Cochrane, EMBASE, and ISI Web of Knowledge databases were searched through 31 May 2014 using the following keywords: psychological/ emotional/mental stress, stress, endothelial dysfunction, endothelium, hypertension, blood pressure, myocardial ischemia, coronary heart disease, ischemic heart disease, and cardiovascular disease. After the duplicates were eliminated, the remaining citations were screened by a twostep process. In the first step, the title and abstract of each article were examined and citations that did not meet any of the inclusion criteria or met one of the exclusion criteria were discarded. In the second step, full-text copies of the
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The primary outcomes were the change of FMD during and after the stress intervention. Decrease or absence of vasodilatation is an indicator of endothelial dysfunction. Statistical analysis Data for the pooled estimate of stress’ effect on endothelial function during and after the stress intervention were analyzed in separate meta-analyses. Heterogeneity among the studies was defined as either a Q statistic of P \ 0.1 or an I-square statistic [50 %. The random-effects model of DerSimonian-Laird was applied when heterogeneity existed [41]. The Mantel–Haenszel fixed-effects method was used instead if no heterogeneity was found. A sensitivity analysis was performed using the leave-one-out approach. When five or more studies were included in the metaanalysis, publication bias was assessed by constructing a
Clin Res Cardiol Fig. 1 The PRISMA flowchart for study selection
funnel plot and by performing the one-sided Egger’s test [42]. A P value \0.05 was considered statistically significant. Evaluations of homogeneity, sensitivity, and the pooled estimates for the differences in the means of FMD were then performed using Comprehensive Meta-Analysis, version 2.0 (Biostat, Englewood, NJ, USA).
Results Search results A flow diagram of article selection is shown in Fig. 1. A total of 148 articles were identified in the initial search. Of these, 19 (12.8 %) articles received full-text review, and 8 (5.4 %) of them met the criteria for inclusion [43–50]. Eleven studies were excluded for not using a stress intervention, presenting no numerical data on the FMD of the participants, or using an intervention (medications or acupuncture) that could have affected a participant’s level of perceived stress. Study characteristics A total of 8 studies enrolling 164 subjects were included in this review to analyze the effects of mental stress on FMD both during and after a stress-inducing task. The characteristics of the eight included studies are summarized in
Table 1. These studies enrolled a total of 164 healthy subjects who resided in Canada, England, Italy, Sweden, Switzerland, or the United States, and the sample sizes ranged 10–39 participants, of which two studies enrolled only males [47, 50]. The stress interventions used are summarized in Table 1. All studies used ultrasound imaging to assess FMD: one study imaged the radial artery [49], and the remaining seven studies imaged the brachial artery [43–48, 50]. The locations imaged and where the blood pressure cuff was placed varied among the studies, and they are listed in Table 2. Outcomes of interest For meta-analysis, only studies that gauged endothelial function by measuring FMD were included. FMD data are shown in Table 2. Four studies reported data at baseline and during the stress intervention [43–46], while 6 studies reported data at baseline and at a specified period of time (range 2–30 min) after the stress intervention [45–50]. Forest plots were generated to determine the overall pooled differences in means for the two primary outcomes of meta-analysis (Figs. 2, 3). Flow-mediated dilation during the stress intervention The individual and overall differences between means of FMD at baseline and during the stress intervention are
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Clin Res Cardiol Table 1 Characteristics of the included studies Author (Reference)
Subjects (n)
Subjects’ age (years)a
Subjects’ gender, M/W (n)
Subjects’ general characteristics
Stress intervention
Szijgyarto [50]
16
19–27
16/0
Healthy, nonsmoking male subjects
Subjects listened to prerecorded instructions, prepared for 10 min, delivered a 5-min speech followed by a 5-min mental arithmetic task
Jambrik [46]
17
19–35
10/7
A mental calculation task
Jambrik [45]
20
19–35
6/14
Healthy volunteers with no known major cardiovascular risk factors Healthy volunteers with no known major cardiovascular risk factors
Gottdiener [43]
39
43 (16)b
18/21
Healthy subjects
An anger recall speech task and a mental arithmetic task
Lind [48]
18
20–25
10/8
Young, healthy, normotensive subjects
A mental arithmetic task
Spieker [49]
23
20–31
NR
Healthy subjects with no known major cardiovascular risk factors
A 3-min mental stress test that asked subjects to indicate the colors of quick flashes of light by pressing a button
Ghiadoni [47]
10
50.4 (9.6)b
10/0
Healthy male subjects
The subjects were falsely accused of shoplifting
Harris [44]
21
23.5b
10/11
Healthy subjects
A standard mental arithmetic task
A mental calculation task that required the subject to perform serial subtraction and multiplication. To induce a higher level of stress, subjects were deceptively told that the result of the test would be used to evaluate their logical-attentive capabilities
M men, NR not reported, SD standard deviation, W women a
Data are presented as the range unless otherwise indicated
b
Data are presented as the mean or mean (SD)
presented in Fig. 2a. Harris et al. reported an increase in FMD relative to baseline during the stress intervention [44]; but Jambrik et al. reported a decrease in FMD [45, 46], and Gottdiener et al. found no significant difference [43]. The Cochran Q statistic (41.97; P \ 0.001) and Isquare statistic (92.9) both revealed obvious heterogeneity among the studies, and thus the random-effects model was used. Our pooled estimate indicates that mean FMD decreased during stress intervention when compared to baseline; however, the difference was not significant [-0.853, 95 % confidence interval (CI): -3.923 to 2.220; P = 0.586]. When the study by Harris et al. [44] was removed and the meta-analysis was repeated (Fig. 2b), both the Cochran Q statistic (23.84; P \ 0.001) and I-square statistic (91.6) revealed heterogeneity among these studies; thus, the random-effects model was used. The difference in mean FMD was still not significant [-2.333, 95 % confidence interval (CI): -4.831 to 0.165; P = 0.067]. The pooled estimate remained statistically not significant after each study was removed in turn in the sensitivity analysis (Table 3). This finding indicates that the pooled data are reliable and no individual study had a disproportionate impact on the results.
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Flow-mediated dilation after the stress intervention The individual and overall differences between means of FMD at baseline and after the stress intervention are presented in Fig. 3. Szijgyarto et al. [50], Jambrik et al. [45, 46], and Spieker et al. [49] all reported decreases in FMD after the stress intervention when compared to baseline, while Lind et al. [48] and Ghiadoni et al. [47] found no significant difference. Both Cochran Q statistic (24.13; P \ 0.001) and I-square statistic (79.28) revealed significant heterogeneity among the studies, thus a randomeffects model was used. When compared to baseline, the mean FMD decreased significantly after the stress intervention (-2.45, 95 % CI: -3.925 to -0.975; P = 0.001). Sensitivity analysis revealed that the pooled estimates of the difference in means remained negative and statistically significant when each study was removed in turn (Table 3). Assessment of publication bias A funnel plot of the mean differences in FMD between baseline and after the stress intervention was made to determine if any of the included studies exhibited publication bias (Fig. 4). The absence of publication bias is
8.68 (SD 3.00)
4.03 (SD 2.04)
2.8 (SE 2.3)
4.1 (SE 1.0)
10.05 (SE 1.59)
Data are pooled from two subgroups
Data are reported as the mean (SD) or mean (SE), as indicated
5.05 (SD 2.20)
5.0 (SE 2.1)
8.0 (SE 1.1)
9.4 (SE 1.2)
4.50 (SD 2.65)
8.94 (SD 3.59)b
11.07 (SD 3.54)b
7.18 (SD 2.86)b
7.92 (SD 2.07)b
7.05 (SD 3.35)b
11.63 (SD 2.94)b
After the stress intervention
4.02 (SE 0.38)
During the stress intervention
5.18 (SE 0.58)
Baseline
FMD (%)a
FMD flow-mediated dilation, SD standard deviation, SE standard error
b
a
21
10
Lind [48]
Harris [44]
39
Gottdiener [43]
23
20
Jambrik [45]
10
17
Jambrik [46]
Ghiadoni [47]
16
Szijgyarto [50]
Spieker [49]
Subjects (n)
Author (Reference)
0.5
30
10
5
4–20 min
4–20 min
10
Elapsed time between the stress intervention and measurement of FMD (min)
Brachial
Brachial
Radial
Brachial
Brachial
Brachial
Brachial
Brachial
Artery assessed for FMD
Table 2 Summary of FMD before, during, and after the stress intervention among the included studies
7 cm proximal to arterial bifurcation
Above elbow on brachial artery
2–3 cm above elbow
7 cm proximal to arterial bifurcation
2–15 cm above elbow
At brachial artery where signal is strongest without interference
Location of Doppler imaging
2 in. below right antecubital fossa
Forearm (below elbow) distal to artery imaged
NA
Around forearm below elbow
5 cm distal to antecubital fossa
Below elbow
Below elbow
Just below antecubital fossa and distal to site of brachial artery ultrasound measurement
Cuff placement
during cuff occlusion and continues for 3 min after cuff deflation
60 s after cuff release
NA
45–90 s after cuff release
2 min
At 60,90,120,150 and 180 s after cuff release
At 1, 1.5, 2, 2.5, and 3 min after cuff release
2 min
Interval between FMD measurement and cuff release
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Fig. 2 Analysis of the effects of stress on immediate FMD. a Metaanalysis of the differences in FMD measured at baseline and during the stress intervention. The mean FMD during the stress intervention was not significantly different from that measured at baseline. b The
corresponding sensitivity analysis performed with the leave-one-out approach. The magnitude and direction of the pooled estimate did not change when any of the four studies was removed. FMD flowmediated dilation
Fig. 3 Analysis of the effects of stress on delayed FMD. a Metaanalysis of the differences in FMD measured at baseline and after the stress intervention. The mean FMD after the stress intervention was significantly less than that measured at baseline. b The corresponding
sensitivity analysis performed with the leave-one-out approach. The magnitude and direction of the pooled estimate did not change when any of the six studies was removed. FMD flow-mediated dilation
indicated when the individual data points form a symmetrical, funnel-shaped distribution. The result of one-tailed Egger’s test (intercept = 0.00425; P = 0.499) indicates that the included studies did not have substantial publication bias.
Discussion
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In our study, mean FMD decreased both during and after the stress intervention when compared to baseline, but the pooled difference in means was not significant for FMD
Clin Res Cardiol Table 3 Sensitivity analysis of the included studies with the leave-one-out approach Comparison
Author (Reference)
Statistics with study removed Point
FMD during the stress intervention vs. baseline
FMD after the stress intervention vs. baseline
Standard error
Variance
Lower limit
Upper limit
Z-value
P value
Jambrik [46]
0.369
1.568
2.458
-2.704
3.442
0.235
0.814
Jambrik [45]
-0.447
1.994
3.977
-4.355
3.462
-0.224
0.823
Gottdiener [43]
-1.007
2.618
6.853
-6.137
4.124
-0.385
0.701
Harris [44]
-2.333
1.275
1.624
-4.831
0.165
-1.831
0.067
Pooled estimate for all 4 studies
-0.853
1.568
2.459
-3.926
2.220
-0.544
0.586
Szijgyarto [50]
-2.799
0.809
0.655
-4.386
-1.213
-3.458
0.001
Jambrik [46]
-2.135
0.885
0.784
-3.871
-0.400
-2.412
0.016
Jambrik [45]
-2.113
0.864
0.746
-3.806
-0.420
-2.446
0.014
Lind [48]
-3.005
0.709
0.503
-4.394
-1.615
-4.238
0.000
Spieker [49]
-2.152
0.856
0.732
-3.829
-0.475
-2.515
0.012
Ghiadoni [47]
-2.470
0.817
0.668
-4.072
-0.868
-3.022
0.003
Pooled estimate for all 6 studies
-2.450
0.753
0.566
-3.925
-0.975
-3.256
0.001
FMD flow-mediated dilation
Fig. 4 Analysis of publication bias of the included studies. Here is a funnel plot to gauge publication bias of the six studies that reported data for FMD after the stress intervention. The results of Egger’s test are shown in the upper right corner of the plot. Publication bias was not detected. FMD flow-mediated dilation
measured during the stress intervention. The lack of significance might be due to the small number of subjects included in the meta-analysis, or from variability, since of the four studies measuring FMD during the stress intervention, only one (Harris et al. [44]) reports increased FMD relative to baseline. This variability among data may result from different experimental protocols regarding the timing of the cuff occlusion in relation to that of the stress test, or the type of stress-inducing task that was administered. Although we suspect a uniform study with a large number of subjects would reveal a significant decrease in FMD during the stress intervention, the inconsistent findings may reflect a true variability in the subjects’ immediate response to acute mental stress. Poitras et al. have
hypothesized that the response to acute mental stress depends on the activity of the sympathetic nervous system (SNS) and the hypothalamic–pituitary–adrenal (HPA) axis, with the most immediate response being regulated primarily by increased SNS output, while the ongoing, delayed response was regulated by increased signaling of cortisol and ET-1 [30]. If this is indeed the case, then our findings of an inconsistent short-term response to acute mental stress suggest that SNS activity, or the vascular response to this activity, is highly individualized. In parallel, the finding of the effect of acute stress on FMD measured several minutes after the stress intervention could mean that the activity of HPA axis is more homogenous within the population of subjects.
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The vasodilatory response is regulated by NO, among other mechanisms [51]. Previous studies have shown that impairment associated with FMD is correlated with the occurrence of cardiac events [52, 53]. Many studies have examined current treatments, risk factors, and causes of CVD [54–60], as well as explored activities and stressrelieving exercises which may slow the progression of CVD [61–66]; but ours may be the first meta-analysis addressing the impact of acute mental stress on endothelial function. A systematic review by Yammine and colleagues had examined effects of acute mental stress on endothelin1 (ET-1) [67], as ET-1 regulates vasoconstriction and has opposing effects on the production of NO [68]. Increased plasma ET-1 was found in patients with CHD, hypertension, and myocardial infarction [69–71]. Five of 10 studies assessed by Yammine et al. reported elevated plasma levels of ET-1 in patients with or at risk for CVD after they were exposed to a stress intervention. We discovered a significant effect of stress on FMD recorded several minutes after the stress intervention, and provided evidence that the deleterious effects of acute stressors can persist for sometime. It is possible that via actions of ET-1 and NO, repeated exposure to stressful events could cause extensive endothelial dysfunction. The effects of different stressful stimuli with different durations on FMD and the role of chronic stress on FMD are worthy for investigation, but are beyond the scope of our study. A recent study by Schmidt et al. exposed sleeping subjects to audio recordings of airplane noise at a level that was loud enough to disrupt sleep and shown to associate with increasing cardiovascular events, before measuring FMD in the following morning [72], and found noise exposure could impact negatively on FMD. By repeating the recording noise 30 or 60 times, they also found a linear relationship between FMD impairment and noise severity. Similar dose/response relationship between mental stress and endothelial dysfunction has been little studied, as evidenced by only 1 of 8 studies included in the current analysis reported a stress intervention with a defined length of time. This study has several limitations. First, the included studies lacked randomized trials and used a variety of stress interventions with different periods of elapsed time (ranging from 30 s to 30 min) between the application of stress and FMD measurement. Second, the studies enrolled healthy individuals who may have had hidden social or familial problems that affected their performance but were not assessed at the time of enrollment. Third, patients were not screened for subclinical atherosclerosis that can potentially affect the baseline arterial diameter and FMD. In addition, we limited our analysis to studies that used FMD for endothelial dysfunction and using other methods to measure endothelial dysfunction may
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produce different findings. Finally, as the study subjects treated with stress intervention were not divided into highand low-stress groups, our analysis could not examine the dose–response relationship between stress and endothelial dysfunction. In conclusion, we conducted a systematic review and meta-analysis of observational studies that provide some evidence that a stressful experience has a delayed, negative impact on the function of the endothelium, and may be important for risk stratification in both healthy subjects and those with pre-existing hypertension or other CVDs. Conflict of interest
None.
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