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Published online before print July 16, 2007, 10.1097/PSY.0b013e3180cc2601
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Psychosomatic Medicine 69:521-528 (2007)
© 2007 American Psychosomatic Society

ORIGINAL ARTICLES

Coronary Artery Disease and Depression: Patients With More Depressive Symptoms Have Lower Cardiovascular Reactivity During Laboratory-Induced Mental Stress

Kaki M. York, PhD, Mustafa Hassan, MD, MMSc, Qin Li, MS, Haihong Li, PhD, Roger B. Fillingim, PhD and David S. Sheps, MD, MSPH

From the Cardiovascular Research (K.M.Y., M.H., D.S.S.), Department of Medicine, University of Florida, Gainesville, Florida; North Florida/South Georgia VA Healthcare System (K.M.Y., M.H., R.B.F., D.S.S.) Gainesville, Florida; Department of Biostatistics (Q.L., H.L.), University of Florida, Gainesville, Florida; Department of Community Dentistry and Behavioral Science (R.B.F.), College of Dentistry, University of Florida, Gainesville, Florida.

Address correspondence and reprint requests to Kaki M. York, Cardiology Research (151), VAMC, 1601 SW Archer Road, Gainesville, FL 32608. E-mail: kaki.york{at}medicine.ufl.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: To investigate the relationship between symptoms of depression and cardiovascular reactivity during mental stress in patients with coronary artery disease (CAD). Depressive symptoms are common in patients with CAD and are related to an increased risk of cardiac events and death. Some researchers have proposed that negative outcomes in depressed patients with CAD may be related to exaggerated cardiovascular reactivity and psychological stress. However, the data are unclear.

Methods: Patients with CAD (n = 128; mean age = 64 years) were recruited for this study. Participants underwent psychological stress testing and 2-day (stress/rest) radionuclide imaging. The Beck Depression Inventory (BDI) results were collected at baseline. Cardiac function data were also gathered and stress data were compared with baseline findings.

Results: The change in systolic blood pressure (SBP) from rest to stress was 47 ± 18 (mean ± standard deviation) mm Hg, diastolic blood pressure (DBP) = 30 ± 11 mm Hg, double product difference (DP) = 5887 ± 3095, and heart rate (HR) = 20 ± 13 beats/minute (p < .001 for all). The BDI score was 8.7 ± 5.6. The BDI score was negatively correlated with all hemodynamic variables, although only significant with stress SBP and DP, and HR and DP changes. BDI scores also predicted changes in HR and DP. HR remained significant in regression analyses controlling for other sample characteristics.

Conclusions: This study showed a negative relationship between depressive symptoms and cardiovascular reactivity to mental stress. In contrast to the mechanism proposed by earlier researchers, this study suggests that decreased cardiovascular reactivity occurs with increased depressive symptomology. The mechanism by which this effect occurs and its clinical significance are still unknown.

Key Words: depression • cardiovascular reactivity • acute mental stress • coronary artery disease

Abbreviations: BDI = Beck Depression Inventory; SBP = systolic blood pressure; DBP = diastolic blood pressure; DP = double product difference; HR = heart rate.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Numerous studies have documented increased rates of depression in patients with coronary artery disease (CAD) (1). Studies suggested that 15% to 20% of patients experience a major depressive episode within 1 year of myocardial infarction (MI) (2,3) and as much as 45% of patients exhibit symptoms consistent with minor depression during initial hospitalization for MI (3). Depression is three times more common in cardiac patients than in the normal population (4). The presence of depressive symptoms post MI has also been associated with increased use of health care services (2), increased risk for adverse cardiac events (5), and death (5,6). Although the presence of clinically diagnosable depressive disorder is an important prognostic indication in these patients, results suggest that even mildly depressed patients are at increased risk for death (7). Relative risk increases with the severity of depression but it is independent of initial CAD severity (7,8) and may persist for as long as 10 years (8).

Although the relationship between depression and CAD is well known, the mechanisms by which depression exerts its effects on cardiac outcomes are less well understood. Several potential mechanisms have been posited, but one area of recent interest has been the regulation of the autonomic nervous system (ANS). Studies have suggested that some patients with cardiovascular disease exhibit decreased parasympathetic (9) and/or increased sympathetic tone (10). Furthermore, this altered ANS activity seems to be related to an increased risk for adverse cardiac events and death (11).

Studies have shown that a subset of patients with CAD experience ischemia with acute mental stress. Mental stress-induced ischemia seems to occur in 35% to 60% of patients with CAD (12–16). It is often accompanied by increased systemic vascular resistance (a marker of sympathetic tone) (12) and seems to be more common in patients with depression (17). Additionally, clinical evidence of an ischemic response to mental stress has been shown to predict adverse cardiac events in patients with CAD (12–16). Researchers propose that altered ANS reactivity may explain the relationship between mental stress-induced ischemia and adverse cardiac outcomes.

The exact mechanism by which this process occurs is still unknown. Therefore, the purpose of this study was to investigate the relationship between symptoms of depression and cardiovascular reactivity to mental stress testing in patients with stable CAD.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Participants
Individuals with CAD were recruited for this study. The sample was drawn from outpatient cardiology clinics affiliated with a regional Veterans Affairs Hospital and a university-based medical center in the southeastern United States. Participants enrolled in the study between fall 2003 and 2005. To be eligible for this study, participants had to be at least 18 years of age; with a documented clinical diagnosis of CAD supported by angiographic evidence; previous coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or MI; or a positive radionuclide, dobutamine, or exercise stress test. Individuals with unstable angina or MI within the last 2 months, severe comorbid medical problems restricting life expectancy to <5 years, pregnant females, and individuals >400 lbs were excluded from participation. Informed consent was obtained from all participants; the study protocol was approved by the University of Florida Institutional Review Board.

Design and Procedure
All participants were tested in the morning after a 12-hour fast. Antianginal medications (ß blockers, calcium-channel blockers, and long-acting nitrates) were withheld for 24 hours before testing. On reporting to the laboratory, participants were asked to complete a series of questionnaires designed to assess baseline demographic and psychosocial characteristics.

The relevant psychosocial measures included the Beck Depression Inventory (BDI) (18), which is a 21-item self-report measure designed to assess symptoms of depression. A 7-item visual analog scale was also used to obtain current emotion/activation ratings. The scale was administered immediately before and after the mental stress procedure. Pre- and post-test values were compared.

On completion of the questionnaire battery, patients were placed in a cool, quiet, darkened room and asked to rest for 30 minutes during which baseline hemodynamic data (heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures) were obtained. Mental stress was then induced via a public speaking task (19). Participants were read a scenario describing a real life hassle (such as a family member with a serious illness, an automobile accident, a dog bite, or an inconsiderate house guest) and asked to "make up a realistic story around" the events described in the scenario. Participants were given 2 minutes to prepare their speech. They were told that their speech would be videotaped and the laboratory staff would replay the tape to rate it for content, quality of speaking style, and duration of speech. They were then asked to speak for 3 minutes. Hemodynamic variable data were also obtained immediately after the speech.

Hemodynamic data were recorded every 5 minutes for the first 25 minutes of the rest period, then at 2-minute intervals for the next two periods, with the final recording at the 30-minute mark. BP values were obtained by a licensed nurse using an automatic oscillometric device (Dynamap Critikon Inc., Tampa, Florida). This device was programmed to automatically calculate BP at the rate described above during the baseline period. The nurse manually operated the machine during the mental stress procedure and returned the device to automatic operations for the recovery period. To approximate the recovery procedure used in clinical stress tests, HR and BP values were calculated at minutes 1, 3, 5, and 10 during the recovery period. HR was obtained from the electrocardiogram, concurrent with BP measurement, throughout this study. Baseline hemodynamic characteristics were compared with peak stress and recovery in subsequent analyses. Hemodynamic data were also used to calculate the double product difference (DP) (peak stress minus rest).

Statistical Analyses
Descriptive analyses were conducted for all baseline demographic and health status variables. Mean and standard deviations values were calculated for continuous variables. Frequencies and percentages were calculated for categorical variables. Descriptive statistics are reported in Table 1 for the total sample. BDI scores were then dichotomized into high BDI (≥14) and low BDI (<14). Sample characteristics were then examined and reported by BDI category (depressed versus nondepressed) (Table 2).


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  		TABLE 1. Demographics and Clinical Characteristics of the Study Sample

 

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  		TABLE 2. Demographics and Clinical Characteristics of the Study Sample by BDI Category (High BDI versus Low BDI)

 

Log transformations were performed on changes in HR ({Delta}HR) and DP ({Delta}DP) to normalize the data. The data were then submitted to a series of linear regression analyses with categorized BDI score as the predictor and {Delta}DP, {Delta}HR, changes in systolic ({Delta}SBP) and diastolic ({Delta}DBP) blood pressures as the criterion variables. As these factors are known to affect cardiovascular reactivity, the effects of the participant's age at the time of assessment, resting hemodynamic variable characteristics, diabetes history, and use of antidepressants, ß blockers, and calcium-channel antagonists were controlled for in these analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
A total of 120 (51 females and 69 males) individuals with CAD participated in this study. Participants ranged in age between 39 and 83 (63 ± 8) years. Participants had a number of comorbid conditions and were taking a variety of cardiovascular medications (Table 1). Approximately 18% of participants were also taking antidepressant medications. These were typically serotonin selective re-uptake inhibitors, serotonin-norepinephrine re-uptake inhibitors, or other second-generation antidepressants.

ß blockers, calcium-channel blockers, and long-acting nitrates were withheld for 24 hours before testing. Although patients were instructed not to take ß blockers before participation in this study, two patients reported that they had not done so and were excluded from further analyses. Antidepressants were not withheld before testing.

The participant's level of depressive symptomology was operationally defined as his or her score on the BDI. Results showed a BDI score of 8.67 ± 5.73.

Preliminary results demonstrated that SBP and DBP, HR, and DP increased significantly from rest to stress (Table 3 and Figures 1–4). All changes were statistically significant at the p < .01 level. The BDI score was negatively correlated with all cardiovascular function variables (Table 4).


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  		TABLE 3. Descriptive Statistics for Hemodynamic and VAMS Variables

 

Figure 17
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  		Figure 1. Scatterplot of change in systolic blood pressure (SBP) by Beck Depression Inventory (BDI) score.

 

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  		TABLE 4. Pearson Correlation Coefficients

 


Figure 27
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  		Figure 2. Scatterplot of change in diastolic blood pressure (DBP) by Beck Depression Inventory (BDI) score.

 


Figure 37
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  		Figure 3. Scatterplot of change in log heart rate (HR) by Beck Depression Inventory (BDI) score.

 


Figure 47
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  		Figure 4. Scatterplot of change in log double product (DP) by Beck Depression Inventory (BDI) score.

 

Visual analogue rating scale measures (VAMS) of immediate mood states and activation also showed increases in several items (tension, sadness, anger, and energy) with concordant decreases in tiredness and relaxation, indicating activation by the task (p < .01 for all (Table 3). BDI scores did not affect VAMS response to mental stress (p > .05 for all).

To test the primary hypothesis that patients with higher levels of depressive symptomology would experience altered cardiovascular reactivity, the data were submitted to a series of linear regression analyses. The mean change in hemodynamic variable (HR, BP, and DP) values were regressed onto the participants' BDI scores (Tables 5–8). Log transformations of change in HR and DP were performed. Results showed that BDI scores predicted 5% of the change in HR (p < .02), and 4% of the change in DP (p < .03). BDI scores continued to predict a significant proportion of the variance in change in HR (p = .05) even after controlling for baseline hemodynamic characteristics, participant's age, diabetes status, and antidepressant, ß blocker and calcium-channel antagonist use. Regression models including BDI scores predicted 16% percent of the variance in change in HR after laboratory-induced mental stress (Table 7) when controlling for the covariates described above. BDI scores did not predict a significant proportion of the change in either SBP or DBP. After controlling for covariates, BDI scores no longer predicted change in DP (Table 8).


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  		TABLE 5. Linear Regression Results: Systolic Blood Pressure

 

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  		TABLE 7. Linear Regression Results: Heart Rate

 

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  		TABLE 8. Linear Regression Results: Double Product

 


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  		TABLE 6. Linear Regression Results: Diastolic Blood Pressure

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
The purpose of the present study was to test the hypothesis that patients with stable CAD and symptoms of depression would have altered cardiovascular reactivity during mental stress testing. The results provided evidence of altered ANS functioning as indicated by the degree of cardiovascular reactivity, although the direction of this effect was different than anticipated. The results of this study suggest that patients with increased depressive symptomology experience decreased cardiovascular reactivity to laboratory-induced mental stress. These results stand in direct contrast to previous research (20).

Numerous studies have documented increased rates of depression in patients with CAD (1) and depressive symptoms in these patients seem to be related to an increased risk for cardiac events and death (5,6). However, the mechanism by which depression affects cardiovascular health is not well understood. Some authors have proposed that altered ANS functioning, as indicated by altered cardiovascular reactivity to stress, may account for negative outcomes in patients with CAD and depressed mood (11). Several studies suggested that depression may be associated with exaggerated cardiovascular reactivity and one recent quantitative review of the literature concluded that depression is a small-to-moderate effect (20). Given the results of previous research, it was expected that patients with greater degrees of depression, as indicated by higher BDI scores, would experience greater cardiovascular reactivity to mental stress. However, our data did not support this conclusion.

The results of this study showed a significant negative relationship between depression and cardiovascular reactivity, such that higher BDI scores were associated with attenuated hemodynamic response to stress. Regression models including BDI scores continued to predict HR response to stress even after controlling for baseline clinical, hemodynamic, and treatment characteristics of the study sample. In a similar study of patients referred for single photon emission computed tomography imaging, Lavoie and colleagues (21) found that individuals who met the criteria for major depressive disorder (MDD) exhibited altered baseline and poststress hemodynamic functioning. In their study, depression was associated with lower baseline BP, lower peak SBP, and attenuated HR, and SBP changes in response to acute exercise-induced stress. Taken together, these results suggested that patients with major depressive disorder may experience blunted cardiovascular reactivity to stress. The results of our study seem to provide additional support for this conclusion.

Possible Mechanisms
Studies of neuroendocrine function are suggestive of increased sympathetic nervous system activation in patients with depression (11). Several studies of patients with MDD but no medical illness have indicated that patients with depression experience increased plasma concentrations of norepinephrine compared with nondepressed controls (22,23). Depression also seems to predict an exaggerated norepinephrine response to acute stress with both physiological and psychological stressors (24,25). In many of these studies, catecholamine levels are correlated with increased resting HR (22,23), which has also been shown to be an independent predictor of adverse cardiac outcomes in patients with CAD (26).

Functional qualities of ß-adrenergic receptor sites are also of particular interest to cardiovascular researchers as these receptors play important roles in directing cardiac contractility, pacing and conduction velocity (27). Studies have shown that long-term exposure to high levels of ß-adrenergic receptor agonists can result in decreased postsynaptic receptor density and sensitivity (28), which has important implications for cardiac function. A growing body of literature suggests that some individuals with high levels of depression may exhibit decreased adrenergic receptor sensitivity (29,30) and density (30–33). Although the initial findings in this area were inconsistent, recent research suggests that some depressed patients have receptor down-regulation (32,34). These differences in ß-adrenergic receptor densities, in particular, may be important for predicting response to treatment (34). Down-regulation of ß receptors on lymphocytes has also been observed in patients with heart failure (35,36), who are chronically exposed to increased norepinephrine levels (37).

In conclusion, this study found that increased depressive symptoms were associated with a decreased hemodynamic response to acute stress. Further, the degree of hemodynamic response to stress was a function of the degree of depressive symptoms. We can only speculate about the mechanism of this effect, but one potential explanation may be decreased ß-adrenergic receptor sensitivity, density, or both. As much of this literature pertains to receptor densities on leukocytes or lymphocytes, it hints at a possible mechanism linking depression, immune function, and cardiovascular health. However, future research is required to determine if the relationship between depression and ß-receptor density/sensitivity in peripheral blood cells is also true of cardiac adrenoreceptor function.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
Received for publication January 24, 2006; revision received April 5, 2007.

This study was supported by Grants HL 070265 (D.S.S.) and HL 072059 (D.S.S.) of the National Heart Lung and Blood Institute. This material is also the result of work supported with resources and the use of facilities at the Department of Veterans Affairs Medical Center, Gainesville, Florida.

Because co-author David S. Sheps is Editor-in-Chief of this journal, the review of this paper was overseen by a guest editor who was chosen by other editors of the journal. Dr. Sheps was not involved in the decision-making process and, like all authors, he was blinded to the identity of the peer reviewers.

DOI:10.1097/PSY.0b013e3180cc2601


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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