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

Numerous studies have documented increased rates of depression in patients with coronary artery disease
(CAD). Studies suggested that 15% to 20% of patients experience a major depressive episode within 1 year of
myocardial infarction (MI)) and as much as 45% of patients exhibit symptoms consistent with minor depression
during initial hospitalization for MI. Depression is three times more common in cardiac patients than in the
normal population. The presence of depressive symptoms post MI has also been associated with increased use of
health care services, increased risk for adverse cardiac events, and death. 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. Relative risk increases with the severity of depression
but it is independent of initial CAD severity and may persist for as long as 10 years. 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 and/or increased sympathetic tone.
Furthermore, this altered ANS activity seems to be related to an increased risk for adverse cardiac events and
death.

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. It is often accompanied by
increased systemic vascular resistance (a marker of sympathetic tone) and seems to be more common in patients
with depression. Additionally, clinical evidence of an ischemic response to mental stress has been shown to
predict adverse cardiac events in patients with CAD. 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.

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), 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. 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).

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.

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. 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. 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. 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 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. 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.
Depression also seems to predict an exaggerated norepinephrine response to acute stress with both physiological
and psychological stressors. In many of these studies, catecholamine levels are correlated with increased resting
HR, which has also been shown to be an independent predictor of adverse cardiac outcomes in patients with
CAD.

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. Studies
have shown that long-term exposure to high levels of ß-adrenergic receptor agonists can result in decreased
postsynaptic receptor density and sensitivity, 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 and density. Although the initial findings in this area were inconsistent, recent research
suggests that some depressed patients have receptor down-regulation. These differences in ß-adrenergic receptor
densities, in particular, may be important for predicting response to treatment. Down-regulation of ß receptors on
lymphocytes has also been observed in patients with heart failure, who are chronically exposed to increased
norepinephrine levels.

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.

REFERRENCES:

Strik J, Lousberg R, Cheriex E, Honig A. One year cumulative incidence of depression

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Hance M, Carney R, Freeland K, Scala J. Depression in patients with coronary heart

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http://www.psychosomaticmedicine.org/cgi/content/full/69/6/521

http://psy.psychiatryonline.org/cgi/content/abstract/51/4/297