Effect of treatment was concentrated among patients who exhibited wall
motion abnormalities (WMA) during mental stress testing prior to treatment.
Among patients with abnormal responses prior to treatment, patients in the
exercise and stress management training groups had better WMA rating scores
at the end of the trial compared with usual care controls (P = .02). Values were adjusted for age, sex, prior myocardial infarction,
pretreatment resting left ventricular ejection fraction, and pretreatment
levels of change in WMA. Missing or unusable posttreatment assessment values
(n = 14) were replaced with pretreatment values. Error bars indicate standard
Blumenthal JA, Sherwood A, Babyak MA, Watkins LL, Waugh R, Georgiades A, Bacon SL, Hayano J, Coleman RE, Hinderliter A. Effects of Exercise and Stress Management Training on Markers of Cardiovascular Risk in Patients With Ischemic Heart DiseaseA Randomized Controlled Trial. JAMA. 2005;293(13):1626-1634. doi:10.1001/jama.293.13.1626
Author Affiliations: Departments of Psychiatry
and Behavioral Sciences (Drs Blumenthal, Sherwood, Babyak, Watkins, Georgiades,
and Bacon), Medicine (Dr Waugh), and Radiology (Dr Coleman), Duke University
Medical Center, Durham, NC; Center for Mental Health and Care, Nagoya City
University Hospital, Nagoya, Japan (Dr Hayano); and Department of Medicine,
University of North Carolina Hospitals, Chapel Hill (Dr Hinderliter).
Context Observational studies have shown that psychosocial factors are associated
with increased risk for cardiovascular morbidity and mortality, but the effects
of behavioral interventions on psychosocial and medical end points remain
Objective To determine the effect of 2 behavioral programs, aerobic exercise training
and stress management training, with routine medical care on psychosocial
functioning and markers of cardiovascular risk.
Design, Setting, and Patients Randomized controlled trial of 134 patients (92 male and 42 female;
aged 40-84 years) with stable ischemic heart disease (IHD) and exercise-induced
myocardial ischemia. Conducted from January 1999 to February 2003.
Interventions Routine medical care (usual care); usual care plus supervised aerobic
exercise training for 35 minutes 3 times per week for 16 weeks; usual care
plus weekly 1.5-hour stress management training for 16 weeks.
Main Outcome Measures Self-reported measures of general distress (General Health Questionnaire
[GHQ]) and depression (Beck Depression Inventory [BDI]); left ventricular
ejection fraction (LVEF) and wall motion abnormalities (WMA); flow-mediated
dilation; and cardiac autonomic control (heart rate variability during deep
breathing and baroreflex sensitivity).
Results Patients in the exercise and stress management groups had lower mean
(SE) BDI scores (exercise: 8.2 [0.6]; stress management: 8.2 [0.6]) vs usual
care (10.1 [0.6]; P = .02); reduced distress by GHQ
scores (exercise: 56.3 [0.9]; stress management: 56.8 [0.9]) vs usual care
(53.6 [0.9]; P = .02); and smaller reductions in
LVEF during mental stress testing (exercise: −0.54% [0.44%]; stress
management: −0.34% [0.45%]) vs usual care (−1.69% [0.46%]; P = .03). Exercise and stress management were associated
with lower mean (SE) WMA rating scores (exercise: 0.20 [0.07]; stress management:
0.10 [0.07]) in a subset of patients with significant stress-induced WMA at
baseline vs usual care (0.36 [0.07]; P = .02). Patients
in the exercise and stress management groups had greater mean (SE) improvements
in flow-mediated dilation (exercise: mean [SD], 5.6% [0.45%]; stress management:
5.2% [0.47%]) vs usual care patients (4.1% [0.48%]; P =
.03). In a subgroup, those receiving stress management showed improved mean
(SE) baroreflex sensitivity (8.2 [0.8] ms/mm Hg) vs usual care (5.1 [0.9]
ms/mm Hg; P = .02) and significant increases in heart
rate variability (193.7 [19.6] ms) vs usual care (132.1 [21.5] ms; P = .04).
Conclusion For patients with stable IHD, exercise and stress management training
reduced emotional distress and improved markers of cardiovascular risk more
than usual medical care alone.
Ischemic heart disease (IHD) is the leading cause of death in the United
States and is rapidly becoming the leading cause of death in developing countries
around the world.1,2 Traditional
biomedical risk factors do not fully account for the development of IHD or
for the triggering of adverse cardiac events. Psychosocial factors are now
recognized as playing a significant and independent role in the development
of IHD and its complications.3,4 Consequently,
efforts to alter psychosocial risk factors, particularly in the setting of
cardiac rehabilitation, have received increased attention. However, the value
of modifying psychosocial risk factors to reduce adverse cardiac events remains
controversial.5,6 Several large-scale
randomized trials failed to demonstrate an advantage for stress management
interventions in reducing cardiac morbidity or mortality,7,8 but
these studies also failed to adequately reduce psychosocial risk factors.
Because emotional distress was not successfully reduced, it was not unexpected
that medical end points also were not affected.
Recently we have shown that exercise and stress management training
reduced mental stress–induced and exercise-induced ischemia9 and resulted in fewer adverse cardiac events compared
with controls over 5 years of follow-up.10 However,
the study was limited by a quasi-experimental design that used a nonrandom
control group. Therefore, the present study was designed to extend our previous
work by comparing the impact of 2 behavioral intervention programs, aerobic
exercise and stress management training, with routine medical care on psychosocial
functioning and select markers of cardiovascular risk in a randomized design.
The markers of risk were selected because of their prognostic relationship
with adverse cardiac events, including mental stress–induced myocardial
ischemia,11- 14 measures
of vascular endothelial function,15- 18 and
cardiac autonomic control.19- 24
Participants were recruited via newspaper, television, and radio advertisements,
letters sent to local physicians, and fliers posted at clinics, community
health fairs, and local shopping centers. The patient sample consisted of
134 patients (92 male and 42 female), aged 40 to 84 years (mean [SD], 63 
years), with documented IHD (by prior myocardial infarction, coronary artery
bypass graft surgery, coronary angioplasty, and/or > 75% stenosis in at least 1 major coronary artery) and evidence of
exercise-induced myocardial ischemia within the past year. Patients with cardiomyopathy,
valvular heart disease, congestive heart failure, severe cardiac arrhythmias,
left bundle-branch block, Wolff-Parkinson-White syndrome, resting systolic
blood pressure higher than 200 mm Hg and diastolic blood pressure higher than
120 mm Hg, left ventricular ejection fraction (LVEF) of less than 30%, or
left main coronary artery stenosis of 50% or higher were excluded. This study
was approved by the institutional review board at Duke University Medical
Center (Durham, NC) and written informed consent was obtained from all participants
prior to their participation. This study was conducted from January 1999 to
February 2003 at a US tertiary care teaching hospital.
Unless medically contraindicated, patients discontinued anti-ischemic
medications (eg, β-blockers, calcium channel blockers, and long-acting
nitrates) at least 48 hours prior to testing. The medication washout period
was at least 5 half-lives of the anti-ischemic drug. Patients restarted their
medications following the completion of the assessments (ie, usually ≤3
days of stopping medications). Twenty-eight patients could not safely discontinue
their medications and were tested on their usual dosage of anti-ischemic drugs.
After a 40-minute rest, mental stress testing was performed in which
patients were presented with 2 mental stress tasks (public speaking and mirror
trace) in counterbalanced order. The speech stressor required participants
to give a speech on a controversial current events topic after 1 minute of
preparation. Sample topics included Do you think cigarette smoking should
be made illegal in all public places? What is your position on gun control?
Should prayer be allowed in public school? Participants were told that the
speech was going to be evaluated by 2 independent judges in which ratings
would be based on organization, speech clarity, and content. The mirror trace
required participants to outline the shape of a star from its reflection in
a mirror. These tasks were used in our previous research25 and
were determined to elicit robust hemodynamic responses and were the most potent
triggers of myocardial ischemia relative to other stressors. Each task lasted
5 minutes, with a 10-minute rest between each stressor. At the conclusion
of the mental stress testing, and after a subsequent 10-minute rest, patients
exercised to exhaustion on a cycle ergometer in the upright position at a
beginning level of 25 W. Exercise workload was increased by 25 W every 2 minutes.
To determine the presence of myocardial ischemia, R-wave–synchronized,
gated equilibrium radionuclide ventriculography with Paragon PBR software
(Medassays Inc, Ann Arbor, Mich) was performed prior to and during each stressor
at 20 frames per cardiac cycle using a gamma camera (Siemens Gamma-Sonics
Inc, Des Plaines, Ill) equipped with a sodium iodide crystal and an all-purpose
collimator. Images were obtained following the labeling of autologous red
blood cells with technetium Tc 99m pertechnetate (Amersham Health, Princeton,
NJ) using the in vivo technique.26 Imaging
was conducted during the last 2 minutes of the rest period, during the first
minute of speech preparation, at 2 and 4 minutes for the speech and mirror
trace stressors, and at peak exercise with the camera in the left anterior
oblique view. The LVEF was obtained using PBR software. Segmental wall motion
of the left ventricle was later assessed visually through the observation
of a continuous-loop video display of the images. Wall motion for each of
the 4 segments was rated by a consensus of at least 2 experienced physicians
blinded to the time of testing (pretreatment or posttreatment) and treatment
group. Segmental wall motion abnormalities (WMA) were rated on a scale from
1 (normal) to 7 (severe dyskinesis). A standard 12-lead electrocardiogram
was monitored continuously and recorded (Quinton Electronics, Seattle, Wash)
at 1-minute intervals during the rest periods, mental stress testing, and
Flow-mediated dilation (FMD) of the brachial artery was assessed following
overnight fasting. Longitudinal B-mode ultrasound images of the brachial artery,
4- to 6-cm proximal to the antecubital crease, were obtained using an Aspen
ultrasound platform (Acuson, Mountain View, Calif) with an 11-MHz linear array
transducer. Images were obtained (1) after 10 minutes of supine relaxation;
(2) during reactive hyperemia, which was induced following inflation of a
pneumatic occlusion cuff placed around the forearm for 5 minutes until suprasystolic
pressure (≈200 mm Hg); and (3) after administration of 400 μg of sublingual
glyceryl trinitrate spray. End-diastolic images were stored on a magnetic,
optical disk and arterial diameters were measured as the distance between
the proximal and distal arterial wall intima-media interfaces using a brachial
analyzer (version 4.0, Medical Imaging Applications LLC, Iowa City, Iowa).
Peak reactive hyperemic response was assessed from 10- to 120-sec postdeflation
of the occlusion cuff; FMD was defined as the maximum percentage change in
arterial diameter relative to resting baseline. Glyceryl trinitrate response
was defined as peak arterial diameter 3 to 5 minutes following administration
and expressed as the percentage change from resting at baseline.
Beat-by-beat systolic blood pressure and heart rate were collected from
patients in the supine position using the Finapres noninvasive blood pressure
monitor (model 2300; Ohmeda, Madison, Wis). For the heart rate variability
measure during deep breathing (HRV-DB), patients were asked to inhale as deeply
as possible for 5 seconds and then to exhale fully for 5 seconds. This was
repeated 10 times and only patients with clear changes in R-R interval across
at least 3 respiratory cycles were used in the analyses. For each respiratory
cycle, the longest R-R interval during expiration and the shortest R-R interval
during inspiration were recorded and the mean (SD) changes were calculated
for analyses. The change in R-R interval during deep breathing is an established
measure in the diagnosis of diabetic autonomic neuropathy.27 Low
levels of HRV-DB are an independent marker of increased mortality risk in
IHD patients and in patients with diabetes.23,24
Cross-spectral analysis was used to estimate baroreflex sensitivity.
Patients breathed spontaneously during recordings used for baroreflex sensitivity
estimation. For these analyses, beat-by-beat blood pressure and R-R interval
(derived as 60 000 per hour) were edited for artifacts, linearly interpolated,
and resampled at a frequency of 4 Hz to generate an equally spaced time series.
A fast Fourier transformation was applied to the interpolated data after the
detrending process and then a Hanning filtering window was applied. Power
spectra were derived for each file using the Welch algorithm, which creates
successive periodograms.28 The baroreflex sensitivity
was estimated from the magnitude of the transfer function relating R-R interval
oscillations to systolic blood pressure across 0.07 to 0.1299 Hz band. Coherence
between systolic blood pressure and R-R interval oscillations was required
to be at least 0.5 Hz to be accepted as estimates of baroreflex control. The
R-R interval oscillations at this frequency band are mediated by vagal control
mechanisms in healthy volunteers in the supine position.29 All
measurements were obtained by experienced personnel blinded to patients’
identity, clinical status, and treatment group.
After patients restarted their anti-ischemic medications, they underwent
a symptom-limited graded exercise treadmill test under continuous electrocardiographic
recording to establish their fitness level and develop an exercise prescription.
A modified Balke protocol was used, in which workloads were increased at a
rate of 1 MET/min.30 Expired air was collected
with a mouthpiece to quantify minute ventilation, oxygen consumption, and
carbon dioxide production with a metabolic cart (model 2900; SensorMedics,
Yorba Linda, Calif). Samples were collected at 20-second intervals and peak
values were determined from an average obtained during the last 60 seconds.
Participants completed a battery of psychosocial questionnaires selected
because of their known association with IHD. Measures included the 21-item
Beck Depression Inventory to assess depressive symptoms,31 the
50-item Cook-Medley Hostility Scale to assess anger and hostile attitudes,32 the 20-item Spielberger Trait Anxiety Inventory to
assess general anxiety,33 and the 24-item General
Health Questionnaire to assess psychiatric symptoms and general distress.34
Once patients completed their baseline assessments, they resumed taking
anti-ischemic medications. Using block randomization software (Resampling
Stats, Arlington, Va), patients were randomly assigned to routine medical
care (usual care); usual care plus supervised aerobic exercise training; or
usual care plus stress management training.
Patients were randomized in blocks of 6 to 8 patients. The randomization
occurred in 2 stages. Patients were randomized to either group A or group
B in a ratio of 1:2. Group A was usual care plus stress management; patients
randomized to group B were randomized to either usual care plus supervised
aerobic exercise training or usual care in a ratio of 1:1. This procedure
is somewhat unconventional because the size of the block was determined by
how many patients were available to be randomized within 1 month of their
baseline assessments, which could vary. Because patients’ cardiac condition
could change over time, we believed that it was important to begin treatment
within 4 weeks of completing their baseline evaluations. Patients were provided
their group assignment in a sealed envelope; staff performing testing were
unaware of the patients’ treatment group assignments.
Exercise Training. Patients were assigned to
usual care plus supervised aerobic exercise training for 35 minutes 3 times
per week for 16 consecutive weeks. Exercise sessions consisted of a 10-minute
warm-up involving stretching and exercise on a stationary bicycle at 50% to
70% of heart rate reserve followed by 35 minutes of walking and jogging at
a target intensity of 70% to 85% of heart rate reserve. Patients recorded
their heart rates at 10-minute intervals throughout each exercise session,
along with ratings of perceived exertion. Each session concluded with 10 minutes
of cool-down stretching exercises.
Stress Management Training. Patients were assigned
to usual care plus weekly 1.5-hour stress management training for 16 weeks.
The stress management training program was based on our prior work,9 which emphasizes a cognitive-social learning model
of behavior. The interaction of the social environment with personality traits
that predispose individuals to respond to situations in particular ways was
highlighted, and the treatment program was based on the notion that emotion
and behavior are largely determined by individuals’ cognitive perceptions.
The program sessions were conducted in a group setting with approximately
8 patients per group. There were 3 key components. First, an educational component
in which participants were provided information about IHD and myocardial ischemia,
the structure and function of the heart, traditional risk factors, and emotional
stress. Stress was defined as an imbalance between excessive demands and inadequate
coping skills. Second, patients underwent skills training, which involved
instruction in specific skills to reduce the affective, behavioral, cognitive,
and physiological components of stress. Therapeutic techniques included graded
task assignments, monitoring irrational automatic thoughts, and generating
alternative interpretations of situations or unrealistic thought patterns.
Patients were instructed in progressive muscle relaxation and imagery techniques,
along with training in assertiveness, problem solving, and time management.
Role-playing also was used. Third, social support was considered to be a key
aspect of the program. Group interaction and social support were encouraged.
Usual Care. Patients in the usual care group
were monitored on a monthly basis to ensure that they had not joined any exercise
or stress management training program. Patients maintained their regular medical
regimens and saw their local cardiologists as needed. No attempt was made
to alter the usual care that these patients received from their personal physicians.
Treatment effects were evaluated using the general linear model with
posttreatment measures serving as the dependent variables, treatment group
as the between-subject factor, and age, prior myocardial infarction, baseline
LVEF, sex, and the corresponding baseline level of the outcome variable as
covariates. Separate models were estimated for the psychosocial outcomes,
LVEF and WMA change during mental stress, and FMD. For each model, we constructed
2 orthogonal contrasts to compare treatments: exercise and stress management
training vs usual care; exercise training vs stress management training. To
enhance the reliability of the mental stress assessments and reduce the number
of statistical tests, the change in LVEF during mental stress was averaged
over the public speaking and mirror trace tasks. Similarly, WMA ratings were
averaged over the 2 tasks.
We also conducted an ancillary analysis of the primary outcomes using
the propensity score approach.35 This approach
attempts to statistically improve the baseline balance on background characteristics
across the groups. These new sets of models included the posttreatment outcome
as the response variable, treatment group assignment as a factor, and the
propensity score and the pretreatment value of the outcome as covariates.
Because the results using propensity scores were essentially the same as our
primary models, only the results of the latter analyses are reported.
We also examined the effect of exercise training on aerobic fitness,
HRV-DB, and baroreflex sensitivity. In these models, we compared groups by
using a priori contrasts, which compared exercise training with usual care
and compared stress management with usual care. We conducted all analyses
using the intent-to-treat principle36; if the
outcome value was missing for a patient, we inserted the baseline value for
that outcome (ie, last observation carried forward). The number of patients
with available posttreatment data is noted in the results section for each
analysis. We also evaluated the extent to which models met assumptions, including
additivity, linearity, and distribution of residuals. It should be noted that
we estimated the sample size based on estimates from our previous trial.9 More specifically, the present study was powered to
detect the 3 largest treatment effects (≈15% greater improvement in the
treatment groups compared with usual care) that we observed previously. Assuming
a 2-sided test and a 5% type I error rate, the estimated power for detecting
these effects in the sample was 0.87 (exercise training effects in wall motion-defined
ischemia during exercise), 0.88 (exercise training effects in wall motion-defined
ischemia during mental stress testing), and 0.72 (stress management effects
on wall motion-defined ischemia during mental stress testing). P<.05 was the level of significance used in this analysis; SAS software
(version 9.1, SAS Institute Inc, Cary, NC) was used for statistical analysis.
Figure 1 shows the patient flow
from initial recruitment screening to assessment after treatment. A total
of 134 patients were eligible for the study and randomized to treatment; 124
(93%) patients completed the study. Demographic characteristics, including
age, sex, family history of hypertension, and race, were similar in the 3
groups (Table 1). Dropouts did not differ
from completers on any background characteristic. In addition, there were
no treatment group differences in medication use. Most patients were taking
aspirin, and the majority took lipid-lowering drugs or β-blockers. Half
of the participants were also taking calcium channel blockers (Table 2).
Among the patients in the usual care plus stress management group, 37
(77%) participated in at least 75% of the sessions; the median number of sessions
attended was 13 (81% of all possible sessions). The median attendance in exercise
training was 43 (89%) of 48 sessions, with 33 (75%) patients attending at
least 75% of the training sessions.
Patients in the usual care plus exercise training group showed a 19%
improvement in treadmill duration compared with 9% in the stress management
group and 1% in the usual care group. Exercise training participants showed
a 6% improvement in peak oxygen consumption per unit time (VO2) compared with a 4% improvement in stress management patients and
a 1% decrement in usual care patients. Compared with patients in the usual
care group, the general linear model analysis revealed that those patients
in the exercise training group showed larger improvements in aerobic fitness
as measured by peak VO2 consumption (1.1 vs −0.2
mL/kg per minute; P = .002) and exercise duration
on the treadmill (70 vs 2 seconds; P = .02).
Patients in the exercise and stress management training groups showed
greater reductions in general distress as measured by the General Health Questionnaire
(P = .02) and in depressive symptoms as measured
by the Beck Depression Inventory (P = .02) compared
with usual care controls (Table 3).
There were no treatment group differences in hostility (measured by the Cook-Medley
Hostility Scale) or anxiety (measured by the Spielberger State-Trait Anxiety
Patients in the usual care group exhibited more ischemia as evidenced
by greater postintervention decrements in LVEF during mental stress testing
compared with those in the exercise and stress management training groups
(P = .03; Table 3). No significant treatment group
differences were observed between patients in the exercise training and stress
management training groups. This pattern was similar with respect to change
in LVEF during exercise training, although the contrast between exercise and
stress management training and usual care was not significant (P = .06; Table 3).
There were no differences among any of the groups on WMA scores during
mental stress testing (Table 3). However, during exercise testing, patients
in the stress management group exhibited fewer new WMA compared with those
in the exercise training or usual care groups (P =
.002; Table 3). While testing model assumptions, we observed that for WMA
during mental stress testing, there was a significant treatment-by-baseline
interaction (P<.001), indicating that the treatment
effect on WMA scores depended on the level of WMA prior to treatment. Figure 2 shows the fitted means from this interaction
model. We examined the contrasts among the exercise and stress management
training groups compared with the usual care group and exercise training compared
with stress management training within each category of pretreatment WMA status.
These analyses indicated that among patients who showed significant stress-induced
WMA before treatment, patients in the exercise and stress management training
groups had lower WMA scores after treatment compared with the usual care controls
(P = .02).
Patients in the exercise and stress management training groups showed
postintervention improvements in FMD compared with those in the usual care
group (P = .03), while patients in the exercise and
stress management training groups did not differ from one another (P = .58; Table 3). Although there was a trend for patients in both
exercise and stress management training groups to exhibit improved glyceryl
trinitrate–mediated dilation compared with usual care controls, the
results did not reach statistical significance (P =
.09; Table 3).
Because the HRV-DB assessments were initiated after the trial began,
data were available for only 47 patients (15 in usual care, 14 in exercise
training, and 18 in stress management). Given the small sample and reduced
statistical power, we adjusted only for baseline level of the outcome variable
and age in these models. The linear model revealed that stress management
was associated with improved HRV-DB. Thus, following stress management training,
patients showed greater changes in R-R interval during forced deep breathing
when compared with patients who were in the usual care group (P = .04; Table 3). Patients in the stress management training group
also showed significant improvements in baroreflex sensitivity compared with
usual care patients (P = .02; Table 3).
Results of this randomized controlled trial demonstrate that behavioral
treatments provide added benefits to routine medical management in patients
with stable IHD. Patients who underwent 4 months of either aerobic exercise
training or stress management training exhibited greater improvements in psychosocial
functioning, including less emotional distress and lower levels of depression
compared with usual care controls. This may be particularly noteworthy insofar
as both distress measured by the General Health Questionnaire and depression
measured by the Beck Depression Inventory are independently associated with
worse prognosis among patients with IHD.37- 39 Participants
in the present study were not preselected on the basis of psychosocial functioning,
and it is possible that patients with higher levels of emotional distress
could have benefited even more from treatment.
Despite the association of depressive symptoms and emotional distress
with adverse cardiovascular events, improvements in psychosocial functioning
are not necessarily associated with improved clinical outcomes. For example,
in the recently completed Enhancing Recovery in Heart Disease (ENRICHD) trial,40 cognitive-behavioral treatment of depressed or socially
isolated patients after acute myocardial infarction led to modest improvements
in psychosocial risk factors, but not to greater reductions in all-cause mortality
or nonfatal cardiac events compared with usual care controls. In addition,
subsequent post hoc analyses revealed that mortality differences between depressed
patients and nondepressed controls did not emerge until 9 to 12 months following
acute myocardial infarction.41 Treating patients
with chronic IHD may be more effective than treating patients with acute coronary
Although the present study was not powered to examine the effects of
the interventions on hard clinical end points, we examined the impact of the
interventions on several cardiovascular risk markers. Patients who underwent
either exercise training or stress management training exhibited smaller reductions
in LVEF during mental stress testing and tended to show smaller reductions
in LVEF during exercise testing compared with usual care controls. For patients
who exhibited WMAs during mental stress testing, stress management also resulted
in reduced WMAs compared with patients in the exercise training group or usual
care controls. Although the magnitude of these differences is relatively small,
it is not necessarily clinically insignificant. Previous studies have reported
that mental stress–induced ischemia is associated with increased risk
for adverse events compared with exercise-induced ischemia.11- 14 A
mental stress–induced decrease in LVEF of only 1% has been associated
with an 8% increase in risk.14 Although patients
in the present study exhibited less ischemia than in our earlier work,25 the present findings are consistent with the pattern
of results that we observed in our previous, nonrandomized trial,9 and therefore represent a partial replication of our
In the present study, patients who received either exercise or stress
management training exhibited more than a 25% improvement in FMD compared
with usual care controls. Several smaller studies have suggested that exercise
interventions may result in improved vascular endothelial function in IHD
patients.42- 44 In
a recent article by Hambrecht et al,45 improved
endothelial function after 4 weeks of exercise training in patients awaiting
coronary artery bypass graft surgery was closely related to increased phosphorylation
of endothelial nitric oxide synthase. Increased bioavailability of nitric
oxide is therefore a likely mechanism accounting for improved FMD following
the exercise intervention in our study.
The mechanism for improved endothelial function associated with stress
management training is not known. However, evidence that FMD is impaired following
brief exposure to standardized laboratory mental stressors46,47 is
consistent with the notion that mental stress may promote atherogenesis.3 The utility of endothelial function assessment as
a pathophysiological marker of disease is supported by findings from prospective
studies demonstrating that endothelial dysfunction predicts adverse cardiovascular
events in patients with IHD.15- 18 Moreover,
results from a recent hypertension intervention trial suggest that improved
FMD in response to treatment is associated with reduced incidence of adverse
cardiovascular events.48 To our knowledge,
our finding that FMD improved following a stress management intervention is
the first to suggest that stress reduction might reduce cardiovascular risk
in patients with IHD in part through favorable effects on vascular endothelial
Patients who received either exercise or stress management training
also exhibited an improvement in baroreflex sensitivity compared with usual
care controls. This finding is important because abnormally low baroreflex
sensitivity has been shown to be associated with worse prognosis in patients
with IHD20- 22 and
may contribute to the risk associated with depression.49 In
contrast, the change in R-R interval during deep breathing did not show an
overall improvement when the 2 active treatment groups were compared with
the usual care group. This appeared to be due to the lack of improvement in
HRV-DB in the exercise training group; the HRV-DB measure improved by approximately
40% in the stress management group. The magnitude of the change in R-R interval
during deep breathing has been known to be predictive of autonomic dysfunction
in diabetes,27 and recent studies have demonstrated
that low levels of HRV-DB predict increased mortality in patients with IHD23 and in patients with diabetes.24 Our
findings suggest that stress management training improves HRV associated with
Our study is limited by its relatively small sample and absence of follow-up
to determine the long-term clinical significance of improved ischemic activity,
autonomic regulation, and endothelial function that we observed among patients
who underwent exercise or stress management training. Although measures of
HRV-DB and baroreflex sensitivity were only obtained on a subset of participants,
results revealed statistically significant improvements in HRV-DB among patients
receiving stress management training. Increased baroreflex sensitivity was
found among patients receiving stress management training compared with usual
care alone. The exercise and stress management training groups also exhibited
improved psychosocial functioning after 4 months of treatment. Because emotional
distress and even mild elevations of depressive symptoms measured by the Beck
Depression Inventory have been associated with adverse outcomes,50 these
findings raise the possibility that the health benefits of improved psychosocial
functioning observed in our prior work9 may
be mediated by improved endothelial function and autonomic control of the
This small randomized clinical trial was not powered to detect differences
in hard clinical end points, and improvement in cardiovascular markers may
not result in reduced clinical events. Caution should be exercised in interpreting
the clinical significance of improvements in intermediate end points.51 In the absence of clinical standards for these measures,
the clinical significance of these changes is uncertain. Ultimately, the long-term
effects of exercise training or stress management will need to be evaluated
prospectively in a larger sample of patients with IHD. However, the present
study provides insight into potential mechanisms by which exercise or stress
management training may be of benefit. Our results suggest that exercise and
stress management training offer considerable promise to patients with stable
IHD through improvement in psychosocial adjustment and by modification of
disease risk markers that may translate into improved clinical outcomes.
Corresponding Author: James A. Blumenthal,
PhD, Department of Psychiatry and Behavioral Sciences, Box 3119, Duke University
Medical Center, Durham, NC 27710 (email@example.com).
Author Contributions: Dr Blumenthal had full
access to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Blumenthal, Sherwood,
Babyak, Hayano, Coleman, Hinderliter.
Acquisition of data: Blumenthal, Sherwood,
Watkins, Waugh, Georgiades, Bacon, Coleman, Hinderliter.
Analysis and interpretation of data: Blumenthal,
Sherwood, Babyak, Watkins, Bacon, Hayano, Coleman, Hinderliter.
Drafting of the manuscript: Blumenthal, Sherwood,
Babyak, Watkins, Waugh.
Critical revision of the manuscript for important
intellectual content: Blumenthal, Sherwood, Babyak, Watkins, Georgiades,
Bacon, Hayano, Coleman, Hinderliter.
Statistical analysis: Blumenthal, Babyak.
Obtained funding: Blumenthal, Sherwood.
Administrative, technical, or material support:
Blumenthal, Sherwood, Babyak, Watkins, Georgiades, Bacon, Hayano, Coleman.
Study supervision: Blumenthal, Sherwood, Babyak,
Waugh, Hayano, Coleman, Hinderliter.
Financial Disclosures: None reported.
Funding/Support: This study was supported by
grants HL59672 and M01-RR-30 from the National Institutes of Health.
Role of the Sponsor: The National Institutes
of Health had no role in the design and conduct of the study, collection and
management of data, or analysis and interpretation of results, and did not
review the manuscript prior to submission.
Acknowledgment: We thank the members of the
Smart Heart data and safety monitoring board—Mark Appelbaum, PhD, Robert
Carney, PhD, David Krantz, PhD, and David Sheps, MD—for their guidance
and advice throughout the trial.