Overview of Stress

Echocardiography: Uses,
Advantages, and Limitations
John S. Gottdiener, MD
umans have probably always been aware that the heart responds
quickly and vigorously to physical and emotional challenge.
Teleologically, our survival has depended more on dynamic
responses to environmental challenge than to basal function. Accordingly,
responses of the cardiovascular system to naturalistic and laboratory
stressors are important measures of cardiovascular function and health.
Beginning with the pulse, and subsequently extending to virtually any
available measure of cardiac pump or electrical function, stress testing has
become a key component of cardiovascular diagnosis and prognosis.
Echocardiography has advantages for stress testing not possessed by
any other diagnostic modality: It directly assesses left ventricular (LV)
contraction, valve function, and intracardiac blood flow. Because echocardiography can identify LV myocardium within known coronary
arterial distributions, the discovery of regional wall motion abnormality
can identify coronary distributions at risk of ischemic injury as well as
those that have already suffered injury. The ischemic cascade (Fig 1)
refers to the sequence of events that occur after an event or intervention
that decreases myocardial perfusion. Because echocardiography can
measure diastolic function, as well as regional and global LV systolic
function, it can detect changes several levels below the repolarization
changes detectable by electrocardiograms (ECG). More recently, echocardiography has shown potential for becoming a robust technique to
assess myocardial perfusion.1 Importantly, as attested to by the widespread availability of echocardiography, its application is relatively
simple and inexpensive.

Reprinted with permission from Prog Cardiovasc Dis 2001;43:315-34.

From the Noninvasive Cardiac Imaging Laboratory, Division of Cardiology, St Francis Hospital, Roslyn, NY,
and the Department of Medicine, State University of New York School of Medicine at Stony Brook, NY.
Curr Probl Cardiol 2003;28:485-516.
0146-2806/2003/$30.00 0
doi:10.1016/j.cpcardiol.2003.10.001

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FIG 1. Ischemic pyramid. Diagnostic tests for ischemia will have sensitivity proportional to whether the
pathophysiology detected is at the base or the tip of the pyramid. (Abbreviations: Fx, function; RVG,
radionuclide ventriculography; Echo, echocardiography)

Historical Background
Although cardiac stress testing cannot determine anatomic narrowing of
the coronary arteries, it can determine the physiologic importance of
coronary luminal obstruction. Of course, stress testing only addresses the
importance of fixed luminal obstruction at the time of the stress test and
will not detect the presence of unstable plaque if the obstruction is minor.
ECG assessment with exercise provides only indirect assessment of
ischemia (Fig 1) and may be of limited sensitivity. Since the demonstration by Tennant and Wiggers2 that coronary ligation in dogs produced
impairment of myocardial performance, direct assessment of regional
myocardial performance has been a goal of cardiologists.
The principal end point of stress echocardiography is the demonstration
of new regional wall motion abnormality during or after the stressor,
corresponding to 1 or more segmental coronary distributions. The
presence of segmental wall motion abnormality presumes inadequate
coronary flow relative to myocardial metabolic demand in those arteries
responsible for distribution of blood to the involved myocardial segments.
The correspondence between segmental decreases in myocardial perfusion and echocardiographically detectable regional wall motion abnormality was shown experimentally 25 years ago by Kerber et al.3
Decreases in myocardial perfusion, measured in microspheres, produced
by partial circumflex coronary artery occlusion resulted in segmental wall
motion abnormality. Importantly, adjacent areas of perfused myocardium
also evidenced hypokinesis, possibly because of tethering to underper486

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TABLE 1. Stress Echocardiography: Imaging Modalities and Physiologic End Points

Two-Dimensional Echocardiography: Transthoracic, Transesophageal
Segmental wall motion
Segmental wall thickening
Global LV function (ejection fraction)
?Myocardial perfusion
Three-Dimensional Echocardiography
Global function
Regional function
Doppler
Aortic systolic flow velocity
Filling velocity

fused segments of the LV wall. Consistent with reperfusion injury,

prolonged coronary occlusion followed by reopening of the vessel did not
result in improvement of wall motion. Since then, in the evaluation of
patients with coronary artery disease (CAD), identification of the culprit
vessel (which of several candidate coronary occlusions is responsible for
the functional alterations of inducible ischemia) has become an important
part of clinical practice. Stress echocardiography has shown itself as an
appropriate method to achieve that purpose.
Even before the widespread availability of 2-dimensional echocardiography in the early 1980s, M-mode echocardiography showed segmental
changes in LV function,4-6 although limited to the midanterior septum
and midposterior wall within the left anterior descending artery and
circumflex distributions, respectively. Moreover, the observation in experimental animal models that wall motion changes with ischemia
occurred before ECG changes7 was extended to humans.8 Hence, the
presence of wall motion abnormality was shown to be more sensitive, as
well as more specific, for the diagnosis of stress-inducible ischemia.
However, the inability of M-mode echocardiography to image more than
a limited extent of the myocardium was a serious impediment for the
detection of regional wall motion abnormality at rest or with physiologic
stressors.

Echocardiographic Techniques
Assessment of global and systolic function with stress echocardiography is almost universally performed with 2-dimensional imaging to assess
effects of stress on wall motion and systolic wall thickening. The imaging
modalities and physiologic end points of stress echocardiography are
highlighted in Table 1.The various stressors used are summarized in
Table 2.
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TABLE 2. Stressors Used in Stress Echocardiography

Physical stressors
Upright treadmill exercise
Supine bicycle exercise
Handgrip
Pacingventricular
Pacingesophageal
Pharmacologic stressors
Dobutamine
Arbutamine
Dipyrdiamole
Adenosine

Continuous
Imaging
During Stress

Clinical
Usefulness

No
Yes
Yes
Yes
Yes

Yes
Yes
Yes
Yes

NOTE. Clinical usefulness values range from (somewhat useful) to (very useful).

Doppler Stress Echocardiography

Doppler echocardiography, used to measure blood flow velocities from
recordings of spectral flow profiles and patterns of blood flow (eg,
valvular regurgitation) with color flow techniques, can also be used with
pharmacologic and exercise stress.9,10 Responses of ejection velocities
and filling velocities to exercise are of interest in the study of patients
with CAD. Increase in systolic blood flow velocity and the rate of ejection
from the LV into the aorta are indicators of the capacity of the LV to
respond to increased demand. LV filling velocities also increase in
response to physiologic need. In one study,10 measurement of peak LV
ejection velocity, acceleration, and acceleration time in the ascending
aorta during dipyridamole stress increased the sensitivity of wall motion
changes for detection of angiographic CAD. Doppler measurements of
blood flow velocity during exercise or pharmacologic stress have not
found widespread application in evaluating patients with ischemic heart
disease because of probable limitations in sensitivity. However, dobutamine or exercise stress Doppler echocardiography can be useful in the
assessment of valvular function, as will be discussed later.

Tissue Doppler With Stress

Recently, important work has been performed with Doppler echocardiography11-15 to measure myocardial tissue velocities at rest and with
stress. Quantification of tissue velocity (Fig 2) may prove to be of use in
supplementing analyses of wall motion and is, in principle, less dependent
on accurate identification of the endocardium. Regional systolic wall
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FIG 2. Tissue velocity spectral Doppler. A new method for assessment of segmental LV function.
Encoding LV wall Doppler shift permits both enhanced imaging of regional wall motion with color flow
display of LV wall Doppler velocities as well as quantification of segmental motion by spectral
Doppler. (Image courtesy of ATL Ultrasound, Bothell, WA.)

velocities, as well as diastolic filling velocities, can be measured and

compared. Additionally, encoding the tissue velocities as images may
improve the qualitative assessment of segmental LV function. The
usefulness of this approach in clinical practice needs to be established in
appropriately designed clinical trials.

Two-Dimensional Echocardiography
Real-time 2-dimensional echocardiography records cross-sectional images of the heart obtained by receiving reflected ultrasound signals
transmitted through various locations (echocardiography windows) on the
chest wall. The quality of those images, however, is affected by a number
of factors. Vigorous cardiac contraction increases translation and rotation
of the heart throughout the scan sector such that different segments of the
LV may be imaged in a given portion of the scan plane thoughout the
cardiac cycle. Respiration changes both the position of the heart relative
to the scan plane and the adequacy of the echocardiography window as
the interposition of air-filled lung, cyclic with respiration, interferes with
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raphy techniques, which allowed selection of single beats gated to the

cardiac cycle for cine-loop display, interpretation of real-time tape
recordings of 2-dimensional echocardiography with exercise was limited
because of a constantly moving image, as well as the difficulty of
assessing regional wall motion at rapid heart rates. Currently, commercially available equipment on echocardiography machines and on offline
units have greatly simplified the acquisition and interpretation of stress
echocardiography. Digitized images can be presented for side-by-side
comparison of prestress and poststress (or intrastress) images at synchronized display rates. Nonetheless, difficulties with rotational and translational effects, respiratory artifact, and echocardiography dropout, particularly of anterior and lateral wall endocardium, can interfere with the
accuracy of stress echocardiography.

Transesophageal Stress Echocardiography

In some patients, it is difficult to acquire transthoracic echocardiographic images of sufficient quality for reliable assessment of regional
wall motion. The principal reasons for this have included lung disease and
aging in which the imposition of the lung between the chest wall and the
heart limits the echocardiographic windows in which imaging can be
effectively performed. Obesity can also limit echogenicity because
impositition of adipose tissue between the transducer and the heart
attenuates the ultrasound beam, decreasing signal/noise ratio. Although
current echocardiographic instrumentation is capable of obtaining good
quality images at greater depths from the signal source than heretofore
possible, there is still a substantial number of obese patients in whom
image quality is not adequate for diagnostic stress echocardiography.
Unfortunately, in some cases of substantial obesity, nuclear stress testing
may also not be possible because these patients may not fit under the
camera. In such cases, transesophageal echocardiography (TEE)16-19 with
pharmacologic stress, most commonly dobutamine, will usually provide
good quality diagnostic images (Fig 3). Apical foreshortening may occur
from the esophageal window and may limit the accuracy of stress TEE.
However, the sensitivity and specificity of dobutamine stress TEE have
been shown to be equivalent or superior to other stress testing modalities,
including treadmill exercise thallium scintigraphy.18 Because TEE requires conscious sedation, dobutamine stress echocardiography (DSE) is
probably not appropriate for routine use. However, in selected cases,
dobutamine stress TEE may be the only way to obtain functional
information on inducible myocardial ischemia.
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FIG 3. LV wall segments as visualized by TEE. All 3 coronary branch distributions are imaged, making
this technique suitable for pharmacologic stress echocardiography. (Abbreviations: ant, anterior; lat,
lateral; post, posterior; sept, septal; inf, inferior; LA, left atrium; RV, right ventricle; Ao, aorta.
Reprinted with permission from the American College of Cardiology [J Am Coll Cardiol, 1994, 24,
pp 1260-1267]16)

Three-Dimensional Echocardiography
Two-dimensional echocardiography performed after exercise requires
the sonographer to sequentially obtain cross-sectional images from 4 to 5
views in 2 principal positions (echocardiography windows) on the chest
wall. It takes time to get the patient from the treadmill to a left lateral
decubitus position on the examination bed and still more time to obtain
the several beats for 4 to5 views in the 2 echocardiography windows.
Substantial experience is required to be able to move the transducer from
one window to another and recapture good quality images of the rapidly
beating heart. Even with experienced and capable sonographers, it may
take 30 to 90 seconds to acquire a complete image data set, during which
time the postexercise heart rate may decrease substantially. Recently,
3-dimensional echocardiographic technology has been developed, including a promising system (Volumetrics, Durham, NC) for real-time 3-dimensional acquisition. Acquisition of only a few beats from a single
window, which can be performed in 4 to 5 seconds, allows complete
reconstruction of the heart in 3 dimensions. Hence, assessments could, in
principle, be performed at higher workload and with more complete
interrogation of the LV than is possible with 2-dimensional techniques.
Although the feasibility of this technique has been shown,20 future
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research will determine whether 3-dimensional exercise echocardiography improves the accuracy of stress echocardiography for detection of
ischemia.

Echocardiographic End Points in Stress

Echocardiography
Assessment of Segmental LV Dysfunction
In many ways, echocardiography is an ideal technique to identify
changes in LV function that occur with ischemia or after myocardial
infarction. Experimental studies have established correspondence of
echocardiographically identified regional LV dysfunction with infarct
size and perfusion deficit.21-27 Clinical research has shown strong
relationships between echocardiographically identified location and magnitude of regional LV dysfunction with pathologic evidence of myocardial infarction, ECG localization of infarct, clinical status, and survival.28-31
In clinical practice, echocardiographic diagnosis of regional wall
motion abnormality at rest or with stress has depended on visual
assessment of single image planes, usually displayed in synchronized,
side-by-side, digital cine-loop format. Judgments are made about the
extent of systolic inward motion of the endocardium. Several segmentation schemes have been advanced to represent myocardial distributions of
the principal coronary arterial branches. A common segmentation scheme
advocated by the American Society of Echocardiography32 uses 16
segments (Fig 4), scored as hyperkinetic, normal, hypokinetic, akinetic, or
dyskinetic. Assignment of numerical values for each segment (1
normal, 2 hypokinetic, 3 akinetic, 4 dyskinetic) allows generation
of a wall motion score averaging the segment scores. All segments
obtained from multiple echocardiography windows may be displayed in a
single bullet diagram (Fig 5). Visual assessment relies on experience and
requires judgments to be made about tethering effects of the base of the
heart on basal myocardial segments and effects of vigorously contracting
segments on affected portions of the contiguous LV. Also, translation and
rotation, as well as whether myocardial endocardium is sufficiently
visualized, affect echocardiographic interpretation. Assessment of regional wall thickening during systole may be more sensitive and specific
than assessment of endocardial motion; however, identification of the
epicardium can be difficult, particularly if the echocardiogram is placed in
still frame mode to allow tracing.
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FIG 4. LV wall segmentation. Sixteen-segment model proposed by the American Society of Echocardiography.32 Multiple views allowing redundant views of some wall segments. (Abbreviations: AS, anterior
septal; ant, anterior; lat, lateral; inf, inferior; post, posterior; IS, inferior septal; LVOT, LV outflow tract;
MVO, mitral valve orifice; LA, left atrium; RA, right atrium; Ao, aortic root. Reprinted with permission from
Oh JK, Seward JB, Tajik AJ, et al: Assessment of ventricular systolic function, in The Echo Manual (ed 2).
Philadelphia, PA, Lippincott Williams & Wilkins, 1999, p 41)

Quantitative Assessment of Regional LV Dysfunction

Computer techniques allowing application of sophisticated graphics
programs to echocardiographic images have been available for several
years. Several segmentation schemes have been developed that allow
generation of multiple radii (radial method) extending from a geometric
center of mass (centroid) to the endocardial and epicardial surfaces or
generation of chords to the endocardium and epicardium generated perpendicular to the LV long-axis (centerline method). These techniques have been
useful in quantitative assessment of regional wall motion and thickness
responses to stress. However, they may not truly make stress echocardiography more objective than visual qualitative assessment because subjective
decisions need to be made on where to determine endocardial and epicardial
contours. Moreover, problems with rotation and translation of an anatomic
plane through the echocardiography scan beam remain, conferring some
degree of ambiguity on segmental localization.
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FIG 5. Bullet display of LV wall segments. All segments are shown on 1 diagram. (Reprinted with
permission from Nidorf SM, Weyman AE: Left ventricle II: Quantification of segmental dysfunction, in
Weyman AE [ed]: Principles and Practice of Echocardiography [ed 2]. Malvern, PA, Lea &
Febiger, 1994, p 647)

Segmental Wall Thickening

Tethering of ischemic segments to intact myocardium may result in
underestimation of ischemic severity. Moreover, the endocardial excursion of nonischemic segments may be limited if they are adjacent to
ischemic segments that move poorly. Hence, overestimation of ischemic
severity can also occur. However, increase in systolic thickness of the
wall is independent of contraction of adjacent segments. Hence, determination of systolic impairment of LV wall thickening with stress should
improve the accuracy of stress echocardiography by allowing discrimination of ischemia from peri-infarct tethering. In practice, this requires
adequate imaging of both the endocardium and epicardium. Moreover, a
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physiologic effect of dobutamine is to decrease the size of the LV cavity.

Hence, the diastolic thickness of the LV wall increases to maintain LV mass
constant. Studies33,34 have shown that percent thickening of the wall may
decrease with dobutamine, even as endocardial excursion increases towards
the geometric center of the LV. Also, this effect may not be uniform
throughout the LV. Nonetheless, it is important to attempt qualitative
assessment of regional wall thickening in response to exercise stress.

Newer Techniques for Regional Wall Motion

Assessment
There has long been interest in computer-assisted automated edge
detection in echocardiography. There are successful algorithms for
identification of some ultrasound interfaces, such as that between brachial
arterial lumen and endothelium. Automated edge detection of the LV
endocardium in real time has also been commercially available for several
years (eg, AQ; Agilent Systems, Andover, MA). Unfortunately, it has
been necessary to have relatively good image quality for real-time edge
detection to work. However, in the presence of good image quality,
automated edge detection has not been necessary and, with intermediate
image quality, detection of interfaces by eye is more successful. Importantly, the 2-dimensional echocardiography approximates real-time tomographic imaging. Although the placement of the ultrasound plane through
the heart may be held steady, the heart nevertheless rotates and translates
in 3 dimensions throughout the cardiac cycle. Hence, points on the LV
endocardium and other portions of the wall may not be consistently
tracked throughout the cardiac cycle. Developing techniques in cardiac
magnetic resonance imaging (MRI)35,36 are promising in allowing such
tissue tagging to be performed so that the same points of myocardium can
be followed throughout the cardiac cycle. In addition to permitting more
precise identification of changes in endocardial wall motion and LV wall
thickeness in systole and diastole, tissue-tagging MRI also has the
potential to study regional changes in stress and strain. This is potentially
a powerful way to precisely quantitate myocardial systolic and diastolic
function at rest and with interventions. Although the clinical usefulness of
this approach remains to be determined, the potential is great.

Provocative Stressors Used With Echocardiography

Exercise Stress
Active physical stressors require the cooperation of the patient to the
extent that the magnitude of stress applied is largely dependent on the
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patients physical condition and motivation to cooperate. Most commonly, treadmill exercise is performed, but other forms of exercise stress
include upright and supine bicycle ergometry and handgrip.
Treadmill. Treadmill exercise echocardiography is the most commonly
performed type of stress echocardiography in the United States. Because
of the impossibility of obtaining diagnostic images during stress, imaging
is actually performed immediately after exercise while the patient is
recumbent, and images are compared with EGCs performed recumbent
just before exercise. This test is popular for several reasons. Treadmill
ECG exercise testing is familiar to all physicians and has been well
accepted for decades. Patients (at least in the United States) can usually
achieve greater workloads with treadmill exercise than bicycle ergometry
because less voluntary effort is needed as the patient is required to
exercise to stay on the moving treadmill belt. Moreover, exercise
performance on the treadmill can be related to activities of daily life in
terms of exercise recommendations, and the ECG response to treadmill
exercise has been well characterized in CAD.
However, limitations of treadmill exercise echocardiography, including
the inability to obtain useful images during exercise and delay in getting
the patient off the treadmill and recording images, may impair the
sensitivity of the postexercise images for the detection of ischemia.
Additionally, marked respiratory effort immediately after exercise and
discomfort in lying down after intense exercise can further complicate
efforts to obtain echocardiographic images of diagnostic quality. Substantial training and effort on the part of the sonographer are required to
obtain good quality images before the heart rate has decreased substantially and the ability to record transient ischemic responses is lost.
Bicycle Ergometry. Bicycle ergometry, particularly while the patient is
supine, is attractive in that it permits relatively stable chest position. This
facilitates echocardiographic assessment during peak exercise, rather than
after exercise, as is the case with treadmill exercise. Hence, supine bicycle
exercise echocardiography should offer superior sensitivity for detection
of inducible ischemia, as opposed to treadmill exercise echocardiography.
Unlike echocardiography performed after treadmill exercise, imaging can
be performed continuously during supine bicycle exercise. Hence, new
wall motion abnormalities can be detected at their onset. In principle, this
allows determination of the ischemic threshold. Additionally, bicycle
exercise echocardiography is potentially safer than treadmill because
detection of ischemia at its onset allows diagnostic testing with lower
workloads than possible with treadmill testing.
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Newer equipment allows rotation of the patient and provides cutouts in

the table surface that further facilitate imaging. However, bicycle ergometry requires disciplined cooperation on the part of the patient to achieve
acceptable workloads. The lack of familiarity of many patients with
cycling, in combination with sedentary lifestyles, can make such cooperation difficult. Most clinical cardiac exercise laboratories already have
motorized treadmills and perform treadmill ECGs routinely. The added
expense and space requirements for an exercise bed or upright ergometer
are also problematic.
Handgrip. Handgrip can produce substantial increases in afterload.
However, it is usually not possible for patients to sustain handgrip for
more than 2 to 4 minutes. Moreover, the total increase in oxygen demand
is not as great as that which can be produced with aerobic exercise.
Studies37,38 have shown good specificity but only limited sensitivity of
handgrip for eliciting echocardiographically detectable myocardial ischemia, and it is not commonly used in the clinical laboratory. However, the
sensitivity of pharmacologic stress echocardiography has been increased
by the addition of handgrip in some studies39,40 although not in others.38

Passive Stress Echocardiography Techniques

Pharmacologic Stress: Dobutamine/Arbutamine,
Dipyridamole/Adenosine. Inotropic Versus Vasodilator
Stress Echocardiography
Early research with inotropic stimulation during ventriculography41,42
established the feasibility of inducing regional wall motion in patients
with CAD. Subsequently, epinephrine ventriculography was replaced by
noninvasive imaging with pharmacologic agents that could produce either
graded increases in inotropic stimulation or mismatches in perfusion by
preferentially vasodilating coronary arteries that were relatively free of
fixed obstructive atheromatous disease.
Dobutamine is the most commonly used agent in the United States for
pharmacologic stress testing. Its effects are complex, including arterial
and venodilation and direct inotropic stimulation. Hence, systolic blood
pressure usually increases, whereas diastolic pressure decreases, although
some patients may evidence a decrease in systolic blood pressure with
dobutamine. When this occurs with exercise, there is usually substantial
global ischemia. With dobutamine, however, hypotension is generally an
effect of peripheral vasodilation and does not usually indicate pump
failure or ischemia. The combination of increased inotropy with decreased afterload and preload commonly results in systolic anterior
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motion of the mitral valve, although clinically important obstruction is

rare in the absence of hypertrophic cardiomyopathy. Common side effects
with dobutamine administration include nervousness, tremor, anxiety, and
palpitations even in the absence of arrhythmia. Serious ventricular
arrhythmias can occur but are rare, and the safety of dobutamine stress
echocardiography has been well established.43-45 Concern may be raised
about the potential of the increased inotropy that occurs with dobutamine
producing systemic embolization in patients with LV thrombus, rupture
of abdominal aortic aneurysm, or excessive increases in heart rate in
patients with atrial fibrillation. However, studies have indicated that DSE
is safe in these special circumstances as well.46-48 Atropine (0.2 to 1.0
mg) is commonly administered at the peak infusion rate of dobutamine
(commonly 40 g/kg/min), if target heart rate has not been achieved, to
enhance the sensitivity of the test. Although side effects of this dose of
atropine are rare, it is nonetheless important to avoid its administration to
patients who have glaucoma or prostatic obstruction.
As with exercise stress, detection of ischemia is predicated on the
inotropic stimulation of ischemic wall segments producing an increase in
oxygen demand in excess of supply, resulting in new wall motion
abnormality or decreased systolic thickening of the LV wall with stress.
However, as discussed previously, decrease in LV preload with dobutamine must inevitably produce increased diastolic wall thickness to
maintain constant LV mass. Hence, percent wall thickening may be
limited by an increase in diastolic thickness relative to systolic thickness.
Moreover, regional differences in relative wall thickening may occur in
normal individuals, possibly because of regional differences in redistribution of stress/strain relationships with hemodynamic unloading.
Arbutamine, also an inotropic agent, with better balance of chronotropic
and inotropic effects, has been advocated in pharmacologic stress
testing,49-51 principally in conjunction with a device programmed to
achieve target heart rate by adjusting infusion rate according to the slope
of heart change. However, the commercial development of this system
was halted, and arbutamine is rarely, if ever, used at present in stress
testing.

Vasodilator (Dipyridamole/Adenosine) Stress

Echocardiography
Dipyridamole is converted to the endogenous vasodilator, adenosine,
which produces ischemia by preferential increase of blood flow to regions
of myocardium served by coronary vessels relatively free of disease.
Stress echocardiography protocols differ somewhat from those used for
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nuclear myocardial perfusion imaging. The sensitivity of dipyridamole

echocardiography can be enhanced by adding a second 2-minute infusion
period of 0.28 mg/kg to the initial 4-minute infusion of 0.56 mg/kg if no
ischemia is evident on echocardiography imaging after the initial dose.52
Adenosine can be administered in a graded infusion because its effects are
more immediate, as are its side effects. Side effects of dipyridamole
include flushing and headache. Because the side effects occur after
completion of the protocol, they do not interfere with completion of the
test. Prolonged myocardial ischemia can generally be terminated by
administration of aminophylline.
In the United States, dipyridamole and adenosine are used more in
nuclear functional testing than in echocardiography. This is because the
greater dilation of nondiseased vessels than diseased vessels, which have
limited vasodilatory capacity, produces large differences in perfusion of
myocardium supplied by normal versus discard vessels, readily detectable
by imaging the distribution of a radioactive tracer within the myocardium.
Detectable mismatches in perfusion may occur even in the absence of
ischemia, and research has shown38 that flow redistribution with dipyridamole thallium imaging may occur in the absence of wall motion
abnormality on echocardiography. When wall motion abnormality does
occur concomitantly with thallium redistribution, the extent of redistribution is greater than in the absence of wall motion abnormality.

Dobutamine Versus Dipyridamole Pharmacologic Stress

Echocardiography
There is a major difference in the clinical practice of pharmacologic
stress echocardiography between European (especially Italian) and American centers. Dipyridamole echocardiography is extensively performed in
Europe, whereas in the United States dobutamine is almost exclusively
used. Reluctance to use dipyridamole in the United States may result from
the theoretical concern that dipyridamole is of primary use in producing
perfusion mismatches between areas of myocardium supplied by normal
versus obstructed coronary arteries and is therefore best detected by
perfusion imaging (at present nuclear rather than echocardiographic in
practice). Although ischemia may occur with vasodilation, the detection
of perfusion mismatch is not ischemia dependent. In contrast, dobutamine
detects the presence of coronary obstruction by producing increases in
demand in excess of supply and is best detected by assessing the response
of regional LV contraction to ischemia. However, summarizing 12
studies53 that directly compared the 2 modalities in the same patients,
little difference was found in the sensitivity or specificity of the 2
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modalities for the detection of angiographically evident CAD. The overall

sensitivity of dipyridamole and dobutamine stress echocardiography were
71% and 77% (P .05), although the sensitivity of dobutamine
echocardiography was substantially greater than dipyridamole echocardiography for the detection of single-vessel CAD (74% v 64%, P .05).
The overall specificity was somewhat higher for dipyridamole (93%) than
dobutamine (87%, P .05), such that the predictive accuracy of the 2
tests did not differ significantly.

Assessment of Stress Effects on Regional Wall

Motion Abnormality Versus Global LV Function
The initial uses of cardiac imaging with radionuclide ventriculography
during exercise stress used either a decrease in LV ejection fraction or
failure to increase LV ejection fraction to a normal degree as an end point
for stress-induced ischemia.54 This may have limited sensitivity for
detection of milder degrees of CAD because compensatory increases of
contractile function in uninvolved segments may mask stress-induced
decreases in contractile function of involved segments. However, with
DSE, decreases in global ejection fraction are rarely seen, even in the
presence of 2- or 3-vessel disease. Hence, global contractile response has
not been a suitable indicator of ischemic response.

Assessment of Myocardial Perfusion

Myocardium, which does not contract but is still perfused, is likely
viable, so assessment of regional perfusion and regional wall motion with
the same technique is of interest. Echocardiography, with newly introduced left-heart contrast agents and improved imaging technology, offers
that promise. The use of echocardiography for assessment of perfusion is
discussed in detail subsequently.1

Stress Echocardiography Doppler for Evaluation of

Valvular Disease
In addition to its primary use for CAD, stress testing is of value in the
evaluation of valvular disease.55-57 Just as the responses of the myocardium to stress are important in health and disease, understanding the
dynamic responses of the cardiac valves to physiologic demands is also of
value.
Aortic Stenosis. Doppler echocardiography has become an important
diagnostic modality for the assessment of valvular stenosis and regurgitation. It has long been appreciated that severe aortic stenosis may exist
in the presence of relatively low valvular gradients if cardiac function is
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severely depressed. Many of these patients improve with aortic valve

replacement. However, in some patients with poor LV function, a
markedly diminished aortic valve area may actually be due in part to
functional aortic stenosis, whereby low stroke volume and force of LV
outflow ejection result in incomplete opening of the leaflets. In one
study,58 17% of patients with poor LV function and aortic valve area
estimated by Gorlin formula to be less than 0.8 cm2 who were sent for
aortic valve replacement were found not to have surgical aortic stenosis
by direct inspection.
Increase in the estimated aortic orifice area with exercise or dobutamine
suggests that the orifice area is not fixed.59 However, several responses to
hemodynamic stress may occur. By using DSE in 18 patients with LV
dysfunction (ejection fraction 0.45) and aortic stenosis, investigators60
found 3 patterns of response. In 7 patients, dobutamine administration
produced increases in LV contraction, transaortic gradient, and valve
resistance but no change in aortic valve area calculated by continuity
equation. In 5 patients who had an increase in LV contraction, there was
also an increase in calculated valve area. Six patients had no wall motion
or hemodynamic response to dobutamine. Among those patients in the
first group who underwent surgery, severe aortic stenosis was confirmed
by direct inspection in all. Surgical assessment of the aortic valve was not
available in the other groups. It may be suggested that patients with
functional aortic stenosis (increased aortic valve area with dobutamine
infusion) will not benefit from aortic valve replacement. In contrast, those
in whom aortic leaflet excursion and area does not increase with
dobutamine, despite an LV contractile response, have fixed anatomic
aortic stenosis and may be candidates for valve replacement. However, in
patients who have no contractile response or change in valve parameters
during dobutamine administration, the interpretation of the test remains
indeterminate. It is important to note that severe aortic stenosis is a
potential contraindication to exercise or dobutamine administration because vasodilation with either of these modalities in the presence of fixed
LV outflow tract obstruction may result in hemodynamic collapse.
Nonetheless, judicious echocardiographic stress testing with adequate
monitoring can be performed safely to assess the anatomic severity of
aortic stenosis.61
Mitral Stenosis. Measurement of the mitral gradient at cardiac catheterization has been performed for decades as part of the assessment of the
functional severity of mitral stenosis. In a parallel fashion, Doppler
echocardiography assessment of mitral valve dynamics during exercise
can provide similar information noninvasively.62-65 Rapid increases in
Curr Probl Cardiol, August 2003

501

Doppler-estimated pressure gradients during mild exercise support

greater functional severity and can assist in evaluation of dyspnea in
patients with mitral stenosis in whom clinical assessment may be made
difficult by the presence of comorbid conditions. Notably, mitral valve
area estimated by pressure half-time may appear to increase during
exercise. This does not necessarily indicate the presence of functional
versus anatomic mitral stenosis, but rather an exercise-related decrease in pressure half-time consequent to alterations in atrialventricular filling relationship resulting in more rapid deceleration of
LV filling velocity.65 Even though mitral valve area estimated by
pressure half-time decreases, it may remain constant when measured
by the continuity equation.

Stress Echocardiography for Preoperative Risk

Assessment
Risk of Vascular Surgery
In patients undergoing peripheral vascular surgery,66 cardiac events
(congestive heart failure, angina, myocardial infarction) are the principal
source of perioperative morbidity and mortality. Although death and
nonfatal myocardial infarction occur in less than 10% of this population,67 CAD contributes substantially to late morbidity and mortality.
Hence, presentation for vascular surgery offers the opportunity for
interventions, not only to avert perioperative cardiac morbidity and
mortality, which have decreased with modern operative and perioperative
care, but also to limit long-term sequelae of CAD. In most cases, exercise
stress is impractical in patients with peripheral vascular disease, and the
largest experience has been obtained with pharmacologic stress echocardiography. In 7 echocardiographic studies of vascular surgery patients
who have intermediate pretest probability of perioperative cardiac events,
dipyridamole or dobutamine stress echocardiography has had a positive
predictive value ranging from 21% to 78% (average, 45%). Importantly,
the negative predictive value of pharmacologic stress echocardiography
(ie, no inducible ischemia with the test) has been close to 100% (100% in
5 studies, 99% and 93% in 2 others).68 Potential concern exists in patients
with abdominal aortic aneurysm about the safety of increasing blood
pressure and force of ejection into the arterial tree during DSE. However,
DSE performed in 98 patients with abdominal aneurysms greater than 4.0
cm in diameter did not produce leakage or rupture.47
502

Curr Probl Cardiol, August 2003

Risk of Nonvascular Surgery

Because the prior probability of CAD is less in patients undergoing
nonvascular surgery than vascular procedures, there has been somewhat
less interest in the use of noninvasive testing to determine cardiac risk in
these patients. In a recent study69 of 530 patients who underwent DSE
before nonvascular surgery, postoperative cardiac events occurred in 6%
(1 death, 31 nonfatal myocardial infarction). All of these had a positive
(ie, new wall motion abnormality) on DSE (sensitivity, 100%; specificity,
63%). Of those with inducible ischemia, receiver operating characteristic
analysis showed that if new wall motion abnormality occurred at less than
60% of the maximum age-predicted heart rate (which was the case in 8%
of patients), then there was a particularly high risk for postoperative
events. In these high-risk patients, postoperative event rates were 43%, in
contrast to 9% for those with ischemia at higher heart rates, and 0% for
those with noninducible ischemia on DSE. Risk stratification with DSE
was superior to that with a common clinical index (Eagle index) based on
age, history of angina pectoris, history of prior myocardial infarction,
history of diabetes, and history of congestive heart failure in which more
than 2 criteria defined high risk and 1 or 2 defined intermediate risk. By
using the Eagle index, the high-risk group (11% of patients) evidenced
adverse events in only 14% of cases, in contrast to 43% of those identified
as high risk with DSE.

Stress Echocardiography in Cardiac Transplantation

Surveillance for CAD is important in patients after cardiac transplantation in whom accelerated coronary vasculopathy of the allograft
remains a major source of mortality after transplantation. Research has
shown that DSE is a useful alternative to serial coronary angiography. In
one study,70 57 of 77 patients (74%) had positive DSE after cardiac
transplantation; 19 of these 57 (33%) had major cardiac events, whereas
no events occurred in those with normal DSE. In another study71 in which
2 serial DSE (the first an average of 37 months after transplantation) were
performed at 18-month intervals, there was high specificity of DSE for
prediction of cardiac events. The lower sensitivity for long-term prediction of cardiac events at the first examination (65%) in contrast to that of
the second examination (92%) was consistent with interval progression of
coronary disease as seen on angiography. Other studies72-74 have also
shown the value of DSE after cardiac transplantation, even in children.75
Moreover, the findings on DSE have corresponded to those of coronary
Curr Probl Cardiol, August 2003

503

intravascular ultrasound,76-78 even with angiographically normal coronary arteries.77

Assessment of Myocardial Viability

Patients may have akinetic segments of myocardium that are nonetheless viable and capable of functional recovery after revascularization. In
patients with CAD and myocardial failure, surgical or catheter-based
revascularization may improve LV function and outcome. Hence, there
may be considerable importance in not only determining the presence of
viable myocardium in patients with myocardial failure, but also in
quantitating how much muscle will be improved with treatment. Clinical
trials to test the hypothesis that viability-guided revascularization improves outcome remain to be performed. However, accurate methods of
determining the relative and absolute quantities of nonviable and viable
myocardium are required to obtain maximum information from such a
trial.
Several strategies are available for determining the presence of viable
myocardium. These include measurement of metabolic activity by showing fluorine F 18 fluorodeoxyglucose (FDG) uptake with positron
emission tomography (PET) or single photon emission tomography
(SPECT); determining the presence of intact microvasculature, which
indicates viable myocardium (eg, with PET, thallium or sestamibi, or
potentially ultrasound contrast perfusion imaging); or by showing contractile capacity with inotropic stimulation (eg, dobutamine at doses lower
than those that produce ischemia). One study79 compared18F FDG uptake
measured by SPECT with thallium Tl 201 reinjection and low-dose DSE
for the ability to detect viability, as determined by restoration of
contraction of myocardial segments within the distribution of revascularized coronary arteries. The sensitivities of 18F FDG, 201Tl reinjection, and
low-dose DSE for identification of contractile recovery were 89%, 93%,
and 85%, respectively, with specificities of 77%, 43%, and 63%,
respectively. However, in hypokinetic segments, the combination of 18F
FDG SPECT and low-dose DSE was the best predictor of recovery. Other
comparisons of low-dose DSE with PET scanning have shown good
sensitivity and specificity for detection of functional recovery of myocardium after revascularization. However, DSE may underestimate the
degree of viability compared with 18F FDG SPECT.80
Although most studies have used subjective visual assessment of
segmental contraction before and after administration of low-dose dobutamine to determine viability, one recent study81 used color tissue Doppler
imaging (TDI), which offers greater objectivity in assessment of segmen504

Curr Probl Cardiol, August 2003

FIG 6. Biphasic response of LV wall thickening to dobutamine. Viable but ischemic myocardium shows
initial improvement in thickening at lower doses (ie, 5 to 10 g/min/kg), followed by loss of
contractile response at higher doses. (Reprinted with permission from Nagueh SF, Zoghbi WA: Stress
echocardiography for the assessment of myocardial ischemia and viability. Curr Probl Cardiol
21:497, 1996)

tal function, to evaluate reversible dysfunction in patients an average of

3 days after acute myocardial infarction. In this study, the sensitivity of
TDI was greater than conventional DSE (89% v 73%, P .05) for the
detection of reversible dysfunction with no difference in specificity or
predictive accuracy. However, at a higher dose of dobutamine (10
g/kg/min), there were no differences in sensitivity but greater ventricular arrhythmia.
The echocardiographic detection of viability is based on an increase in
wall thickening or endocardial excursion at low doses of dobutamine (Fig
6). Some patients will have a biphasic response in which the initial
increase in wall thickening at low dose is followed by a decrease at higher
infusion rates, suggestive of viability and ischemia. Importantly, there
may be apparent contradictions between the results of nuclear perfusion
imaging and echocardiographic assessment of viability. Rather than
representing methodologic artifact, these differences may reflect the
admixture of viable and infarcted myocardium within a myocardial
segment. The subendocardium contributes more than the subepicardium
to myocardial contraction. Hence, subendocardial infarction in the presence of viable subepicardium can present with the presence of segmental
perfusion in the absence of endocardial contraction or wall thickening
(Fig 7). Moreover, the effects of therapeutic reperfusion may be disappointing in such cases.

Stress Echocardiography Versus Stress Nuclear

Because dipyridamole produces regional differences in perfusion and
dobutamine produces segmental decreases in LV wall motion, perfusion
imaging (nuclear or PET scanning at present, perhaps echocardiography
in the future) should be best suited for dipyridamole testing, whereas
Curr Probl Cardiol, August 2003

505

FIG 7. Mismatch between myocardial perfusion and contraction (eg, preserved perfusion of involved
wall segments on thallium or sestamibi imaging despite lack of segmental contractile response to
dobutamine) can occur in the presence of subendocardial infarct with preserved subepicardial
perfusion (middle panel). (Abbreviations: revasc, revascularization; TL, thallium; MCE, myocardial
contrast echocardiography. Reprinted with permission from Shan K, Nagueh SF, Zoghbi WA:
Assessment of myocardial. viability with stress echocardiography. Cardiol Clin 17:547, 1999)
TABLE 3. Nuclear Versus Echocardiography Stress Imaging for the Detection of CAD
Author

Year

Simonetti et al83
Perin et al84
Pozzoli et al85
Salustri et al86
Amanullah et al87
Forster et al88
Gunalp et al89
Marwick et al90
Marwick et al90
Quinones et al91
Hoffman et al92
Hoffman
Pirelli et al93
Mairesse et al94
Hoffman et al95
Elhendy et al96
Santoro et al97
Santoro et al97
Parodi et al98
Fragrasso et al99
Fragrasso
Average

1991
1991
1991
1992
1993
1993
1993
1993
1993
1993
1993

35
25
75
44
40
21
27
217
97
289
66

1993
1994
1996
1998
1998

50
129
50
84
33

1999
1999

101
101

Echocardiography
Method

Nuclear Method

Dipyr
Dipyr
Ex-Bs
Ex-Bu
Aden
DSE
DSE
DSE
Aden
Ex-T
DSE
Ex-T
Dipyr
DSE
DSE
DSE
Dipyr
DSE
Dipyr
Dipyr
DSE

Planar-Th
SPECT-Th
SPECT-MIBI
SPECT-Th/MIBI
SPECT-MIBI
SPECT-MIBI
SPECT-Th
SPECT-MIBI
SPECT-MIBI
SPECT-MIBI
SPECT-MIBI
SPECT-MIBI
Ex-Th
Ex SPECT-MIBI
Dob-MIBI
Dob-SPECT MIBI
Dipyr SPECT MIBI
Dob SPECT MIBI
Dipyr SPECT MIBI
Ex-SPECT-MIBI
Ex-SPECT-MIBI

Abbreviations: Dipyr, dipyridamole; Aden, adenosine; Dob, dobutamine; Ex-Bs, supine exercise
bicycle; Ex-Bu, upright exercise bicycle; Ex-T, treadmill exercise; Th, thallium; MIBI, sestamibi.

echocardiography (or MRI) should be preferable for use with dobutamine

testing. Moreover, because ischemia is not necessary to produce segmental perfusion differences, dipyridamole perfusion imaging should show
506

Curr Probl Cardiol, August 2003

FIG 8. Degree of interinstitutional agreement in dobutamine stress echocardiography interpretation.82

Agreement was 100% in patients with excellent study quality (Bar A) in contrast to only 43% in
patients with the lowest image grade E. Of the 150 patients studies, a third were in the lowest 2 image
quality categories. (Modified and reprinted with permission from the American College of Cardiology
[J Am Coll Cardiol, 1996, 27, pp 330-336]82)

TABLE 3. Continued
Sensitivity (%)

Specificity (%)

Echocardiography

Nuclear

Echocardiography

Nuclear

86
58
71
86
74
75
84
72
58

91
95
84
83
94
83
94
76
86

79
80
75
76
91
73
55
61
78
61
88
70

89

92
100
96
85
100

88
83
87
88
81
87
90
89
81
83
96
96
76
91
80
88

100
50
88
64
100

88
67
71
81
71

84
65
75
83
89
81
90
36

77

83
76
94
67
97
91
79
98
98
87

greater sensitivity for detection of CAD than wall motion imaging with
dobutamine. Because impairment of segmental LV wall motion with
dobutamine is dependent on the production of ischemia, wall motion
Curr Probl Cardiol, August 2003

507

imaging with dobutamine should have particular prognostic value in

patients with established CAD in whom outcome is dependent on the
ischemic burden. Hence, in comparing studies of dobutamine stress
echocardiography with dipyridamole nuclear perfusion scintigraphy, it is
important to consider whether prediction of anatomic coronary disease,
detection of regional inducible ischemia, or prognostic value is being
assessed.
To the extent that nuclear and echocardiography stress tests have
overlapping purposes, comparison of their relative value is in order. There
is ample literature (Table 3) comparing the value of these tests for
detection of angiographically detectable CAD and comparing their
predictive value for cardiac events. There are also some studies that have
compared the detection of ischemia with PET techniques as a gold
standard. Despite differences in individual studies, there has been
approximate comparability of both nuclear and echocardiographic stress
imaging for detection of coronary disease and for prognosis in populations at risk. However, it is important to note that such comparisons are
performed in laboratory settings, which may be idealized relative to the
conditions of medical practice. Image quality may vary substantially
between laboratories and even between patients in the same laboratory. In
multicenter studies, it has been shown82 that the interreader agreement is
markedly decreased in the presence of poor image quality (Fig 8).
Moreover, there is possibly a certain natural enthusiasm and advocacy on
the part of investigators with particular expertise and experience with one
technique over another.
Hence, the application of these studies to medical practice should be
informed by an assessment of the accuracy and reliability of the
locally available echocardiographic and cardiac nuclear facilities, as
well as the dedicated expertise available for both. This may be difficult
to achieve in practice. However, there has been substantial interest on
the part of cardiac nuclear and echocardiography laboratories in
improving quality, which has been encouraged by the growth of
accreditation groups such as the Intersocietal Commission for Accreditation of Echocardiography Laboratories and the Intersocietal Commission for Accreditation of Nuclear Laboratories. Increasing application of laboratory quality-control measures, such as comparison of
diagnostic tests with appropriate gold standards, specialized training,
and continuing medical education of physicians and sonographers (or
nuclear technologists), will do much to improve the clinical value of
cardiac stress imaging.
508

Curr Probl Cardiol, August 2003

Summary
An important advantage of echocardiograpy is its ability to assess
segmental LV function continuously and simply on a beat-by-beat basis.
Echocardiography performed at rest, in comparison with vasodilator or
inotropic stress, has proven itself a clinically useful test to assess the
presence of myocardial ischemia and viability and for risk assessment in
patients undergoing cardiac and noncardiac surgery. In comparison with
competing nuclear techniques, echocardiography confers incremental
information on valvular disease. The detection of aortic stenosis and
mitral regurgitation is of substantial importance, particularly in aging
populations and in patients with severe LV dysfunction and secondary
mitral regurgitation. Moreover, the baseline echocardiogram can provide
information about LV hypertrophy, diastolic dysfunction, and pericardial
effusion, which may be of importance in some cases. However, subjectivity in assessment of wall motion and the current clinical immaturity of
perfusion assessment with echocardiography are present limitations.
Attention to reproducibility and other aspects of quality control are key
elements for both nuclear and echocardiography laboratories. The choice
of either echocardiography or nuclear techniques for evaluation of
patients with CAD should, in large part, be based on the relative
experience and expertise available to the practitioner. Evolving strategies
for revascularization, particularly in patients with severe LV dysfunction,
will require accurate, reliable, and possibly, quantitative assessment of
myocardial viability and ischemia. The demands placed on quality in
noninvasive techniques will therefore increase for both echocardiography
and nuclear cardiology laboratories.

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