Exercise-Simulating Agents

The exercise simulators include dobutamine and other sympathomimetic agents, pacing, and atropine (usually used as an adjunct to the other approaches), all of which increase cardiac work and myocardial oxygen requirement. The induction of ischemia and regional dysfunction reflects the inability of the diseased coronary circulation to respond to this increased oxygen demand, a process that parallels the response to exercise. Because increased cardiac workload and oxygen demand is the usual mechanism underlying ischemia in most ambulatory situations, the exercise-simulating agents are often considered to be a more physiologic means of stressing the heart. However, additional mechanisms include effects on cardiac metabolism producing an “oxygen-wasting” effect² and concurrent “supply” ischemia due to reduction of subendocardial perfusion and maldistribution of coronary flow.

Vasoactive Agents

The use of dipyridamole in combination with myocardial perfusion imaging is based on the induction of maximal coronary vasodilation in all territories. Flow heterogeneities (and therefore apparent perfusion defects) develop if a coronary stenosis limits the regional hyperemic response.³ Of note, this process may not involve the provocation of ischemia in a functional or metabolic sense. In contrast, the development of regional wall motion abnormalities at stress echocardiography necessitates the induction of ischemia.

The mechanism of vasodilator-induced wall motion abnormalities has been attributed to coronary steal.³ Traditionally, horizontal steal involves blood flowing to nonstenosed from stenosed territory, owing to reduced collateral flow into the stenosed territory because of depressurization of vessels supplying the collaterals due to increased runoff. Vertical steal occurs because vasodilator-induced depressurization of the microcirculation causes subendocardial vessels to collapse under the greater extravascular pressure in this region and “steal” flow to the subepicardium from the subendocardium. However, in experimental studies, steal appears less important than previously proposed, and vasodilator-induced ischemia has been attributed to the combination of reduced endocardial myocardial blood flow reserve with increased myocardial oxygen demand caused by hypotension and reflex tachycardia.⁴ The administration of atropine or increased sympathetic activity secondary to angina may augment this process. Systemic hypotension may certainly accentuate hypoperfusion, as driving pressure is the main determinant of myocardial perfusion when vasodilator reserve is exhausted. Stenosis “collapse” may be provoked if profound microcirculatory vasodilation causes a reduction of lateral pressure induced by increased flow.

Agents Used to Identify Myocardial Viability

In the presence of dysfunctional but viable myocardium, regional function is enhanced by the inotropic effect of low-dose dobutamine. This appears to require both recruitable perfusion and an increment in metabolism. Viable myocardium supplied by a patent infarct-related vessel (generally corresponding to stunned myocardium) demonstrates a sustained improvement during the infusion, which then reverses after the test. Viable tissue supplied by a stenosed infarct-related artery (which may involve stunned or chronically malperfused tissue) is characterized by an initial improvement, occurring at low doses (less than 20 mcg/kg/min), or low heart rates, or both, followed by deterioration of regional function as the chronotropic effect becomes more prominent and myocardial work increases. If the region is supplied by a critically stenosed artery, however, it may be possible for the territory to become ischemic before there is a noticeable enhancement of contractility. Moreover, the ability of the myocardium to thicken is determined by the amount of infarcted tissue within the segment.

Myocardial viability may also be inferred from the contractile response to dipyridamole. The mechanism of this is also putative but probably relates to myocardial congestion with interstitial fluid due to vasodilation. A so-called mini-Starling effect may be caused by this congestive process, producing additional tension on the myofibrils.

Exercise-Simulating Agents

The exercise-simulating agents include dobutamine, dopamine, epinephrine, and isoproterenol. Of these, dobutamine has become the most commonly administered exercise-simulating agent, and the majority of published data on pharmacologic stress echocardiography have involved this agent. Although other sympathomimetic agents have been used for stress testing, dopamine may cause localized limb ischemia due to vasoconstriction, and epinephrine and isoproterenol are probably the more arrhythmogenic.

Dobutamine is predominantly a beta-1 agonist; normal areas of myocardium become hyperkinetic in response to its inotropic effect. Segments supplied by a stenosed coronary artery may become akinetic or dyskinetic, but more subtly, and are unable to augment their thickening and excursion. Vasodilation and chronotropy appear at higher doses, usually at the 20 mcg/kg/min level of the routine dobutamine stress protocols, reflecting the stimulation of other receptors to a lesser degree. This chronotropic response appears to be the most important factor in terms of precipitating ischemia. Most dobutamine stress protocols cause a mean heart rate increment of 40 to 50 beats per minute and mean peak heart rates of 110 to 120 beats per minute.⁵ However, reflex bradycardia may occur in response to hypertension. Blood pressure normally rises in response to the inotropic effect of the drug, but high doses cause vasodilation and therefore cause blood pressure to fall at peak doses. Increases in myocardial oxygen demand due to increased cardiac work, as well as a weak vasodilator effect, lead to the development of coronary hyperemia in territories supplied by normal coronary arteries. Although this response is probably less than that induced by coronary vasodilators, the coronary hyperemic response to dobutamine stress permits its use with perfusion imaging, both scintigraphic and with microbubbles.⁶ The detection of myocardial perfusion defects in the presence of coronary disease may be augmented by partial volume effects due to thinning of the ischemic wall.

Vasoactive Agents

The principal coronary vasodilators are dipyridamole, adenosine, and regadenoson, which differ with respect to the onset and duration of their effects. Dipyridamole increases endogenous adenosine levels by reducing cellular reuptake and metabolism, and thereby acts indirectly.³ This indirect mechanism causes some delay between the administration of this agent and the timing of peak vasodilation, and this indirect action may account for interindividual variations in the magnitude of its effects. Adenosine acts directly on the vasculature, its vasodilator efficacy being equivalent to that of papaverine. The potency and speed of onset of adenosine cause its side effects to be more intense but also more short-lived than those of dipyridamole. By comparison to adenosine, the new A(2A)-specific receptor agonists have fewer complications but a similar mechanism of action.⁷ As with adenosine, however, their primary vasodilator role makes them more attractive for perfusion imaging than for wall motion assessment.

Ergonovine stress echocardiography is not widely practiced, although its use as a test for coronary spasm is well validated. This agent has a direct effect on the vessel; responsiveness to acetylcholine may be related to loss of nitric oxide production at the site of disease.

Exercise Simulation Using Pacing Stress

Several nonpharmacologic stressors have been used, including “physiologic” stresses such as the cold pressor test, which are poorly tolerated. Pacing is an alternative means of increasing cardiac work; pacing-induced tachycardia increases myocardial oxygen consumption and causes myocardial ischemia in the setting of significant coronary stenoses. The reduction of subendocardial perfusion with pacing may also contribute to the development of ischemia.

Ventricular pacing is not favored, as it causes both abnormal regional contractility and abnormal perfusion, so that pacing stress techniques generally involve atrial stimulation, either transvenously or via the esophagus. Of the transesophageal pacing approaches, the “pill” electrode is effective but may cause significant discomfort. Attachment of pacing electrodes to transesophageal echocardiography (TEE) probes has been reported in trials but has not moved into commercial production. A small esophageal pacing catheter offers enhanced contact between the electrodes and the esophagus. The technique causes less discomfort than other pacing techniques because of the presence of smaller pacing thresholds but is not widely used.

Pacing stress may be useful in patients in whom the pharmacologic approaches are contraindicated or associated with side effects. Additional attractions that might justify its use in preference to pharmacologic testing include the capacity to achieve a target heart rate in virtually all patients, the potential to immediately terminate the tachycardia if the patient develops complications (in contrast to pharmacologic methods, which require a period of time for the effects to dissipate), and the ability to perform measurements in the ischemic ventricle at a low heart rate (after cessation of pacing). Using atrial pacing stress, ischemic myocardium has been shown to have reduced ventricular compliance. Sudden termination of stress during ischemia may also be of value in the combination of stress testing with color flow Doppler, as the use of low frame rates may pose a problem at high heart rates. However, despite the benefits of transesophageal atrial pacing, its availability for many years, and recent data showing correlation with dobutamine stress echocardiography (DSE) despite a shorter test duration and better patient tolerance, this technique has not become widely used because it remains somewhat invasive.

Combined Approaches

Atropine reduces the depressant effect of vagal stimulation on heart rate and may be particularly useful when reflex reduction of the heart rate occurs in response to blood pressure elevation. Atropine is combined with dobutamine in patients who fail to develop an adequate degree of tachycardia in response to dobutamine, the most common situation involving patients taking beta receptor antagonists. Tachycardia (and therefore ischemia due to increased oxygen demand) may be obtained by combining atropine with dipyridamole.^8,9 In both circumstances, the addition of atropine to other stressors has been associated with an increment in sensitivity. Indeed, there is a trend toward earlier use of atropine during the dobutamine protocol, especially in beta-blocked patients. Early administration of atropine should not be allowed to interfere with the assessment of the low-dose response, so we do not administer this agent before the end of the 20 mcg/kg/min dose. A simple guide is that patients who fail to attain a heart rate of 70 beats per minute, or fail to increase heart rate by 5 beats per minute at this dose, rarely achieve target heart rate and might as well have the atropine early so as to avoid a prolonged test.

Combinations of dobutamine and dipyridamole have been described but are not used, because although the combination has afforded higher levels of sensitivity than the individual tests can provide, this is obtained at the cost of an unacceptably long stress protocol.

Image Acquisition

The technical challenges of pharmacologic and pacing stress, although less extreme than those posed by exercise echocardiography, mandate the use of the best available equipment. The development of harmonic imaging has had a major impact on endocardial visualization¹⁰ and therefore on the feasibility of stress echocardiography.¹¹ Although very few patients (less than 2%) have completely uninterpretable images, failure to detect the endocardium in every myocardial segment is very common, and contrast is indicated if two segments are obscured (Fig. 16-1).

Figure 16-1 Use of myocardial contrast for LV opacification during stress echocardiography.

Compared with harmonic imaging (A), the postcontrast end-diastolic apical four-chamber image (B) shows significant improvement of lateral wall resolution.

Typically, transthoracic images are obtained in the standard views (parasternal long- and short-axis and apical four- and two-chamber). Two additional views are helpful—an apical long-axis view, which may overcome technical problems with parasternal imaging, and an apical short-axis view. Of the complementary imaging techniques, including contrast, strain, and three-dimensional (3D) imaging (see later section), the evaluation of coronary flow reserve in the left anterior descending artery is the simplest addition, although this seems to be most feasible in combination with adenosine.¹²

TEE has been employed in combination with both pharmacologic and pacing stress, usually for patients with inadequate transthoracic images. During transesophageal imaging with pharmacologic stress, we approximate the standard imaging planes as closely as possible by recording transverse and longitudinal esophageal and transgastric short- and long-axis views. During pacing with electrodes attached to the TEE probe, the need to stimulate the esophagus inhibits the ability to move the transducer, so that imaging is performed in the transgastric planes only.

Although the constraints of a busy stress echocardiography schedule may preclude the performance of a detailed examination in every patient, a “screening” M-mode, pulsed wave (especially for LV inflow), and color Doppler echocardiographic examination should be performed at the beginning of every study. According to the setting, tissue Doppler images maybe helpful at baseline for the assessment of filling pressure¹³ and dyssynchrony.¹⁴ Time should also be taken to optimize two-dimensional (2D) echocardiographic images and gain settings (for endocardial detection) and to zoom on the ventricles (to obtain the best spatial resolution and frame rate). During the stress, the patient is imaged continuously, and the images are stored in digital clips. When the study is performed for the diagnosis of coronary disease, we favor a multiscreen display to show as many stages as possible, as changes may be transient. Many types of viewing software do not permit this. If so, the minimum default quad-screen display should include a resting image, a low-dose image (10 mcg/kg/min dobutamine, 0.56 mg/kg dipyridamole, or a small heart rate increment with pacing), a high-dose image (40 mcg/kg/min dobutamine or 0.84 mg/kg dipyridamole with or without atropine), and an early poststress image. The ability to save images at multiple stages enables easy alteration of this display. For example, when the clinical question pertains to the possibility of viable myocardium, the display could include two low-dose images (5 and 10 mcg/kg/min dobutamine) and one high-dose image.

Image Processing

Digital techniques are critical for successful interpretation and archiving of stress echocardiograms. Digital image processing facilitates image display and interpretation by allowing a side-by-side display of resting, low-dose, and high-dose images, as well as the ability to review individual frames (which is useful to evaluate the temporal sequence of contraction). However, all studies should also be recorded in continuous format. Traditionally, this involved use of videotape, to provide a backup in case technical problems with the digital capture (especially triggering) or corruption of the archived data threaten loss of the study. Indeed, routine review of tape has a significant impact on diagnosis, probably by permitting review of off-axis images and regions that are not adequately represented by saving a single cardiac cycle. Although videotape is now rarely available in the echocardiography lab, continuous digital capture is an alternative.

Qualitative Interpretation

The interpretation of stress echocardiograms for clinical purposes is based on a qualitative evaluation of regional function at rest and stress.¹⁵ Some standardization is obtained by scoring regional wall motion and thickening in a number of segments. The American Heart Association has proposed a unified 17-segment model that includes the apical cap, to facilitate comparison between imaging modalities.¹⁶ Although this template ignores the small but important detail that the true apex is often not identified at echocardiography, its role as the standard should make its use preferred to the older 16-segment model (anterior, septal, lateral, and inferior at the apex, with these segments as well as anteroseptal and posterior segments at the base and midpapillary muscle level). Despite this standardization, however, the expertise of the physician interpreting the test is critical, and even accomplished echocardiographers require a significant learning period. In a study of echocardiographers learning dipyridamole stress echocardiography, Picano and colleagues reported that 100 supervised studies were required to bring the accuracy of “novices” to the level of “experts.” Despite many technical advances in stress echocardiography in the past two decades, this learning curve remains important.

The standard qualitative algorithm for interpretation of pharmacologic stress echocardiography is summarized in Table 16-1. With the exception of the low-dose responses, which denote myocardial viability, it may also be applied to pacing or other stressors.

TABLE 16-1 Interpretation of Myocardial Viability and Ischemia Using Dobutamine Echocardiography

Regional wall motion at rest may be classified as normal, hypokinetic, akinetic, or dyskinetic. Severe hypokinesia may be difficult to distinguish from akinesia; a useful guide is based on endocardial excursion, with less than 2 mm identifying akinesia and less than 5 mm indicating hypokinesia. Regions that fail to thicken or that move only in late systole (after movement of the adjacent myocardium) may be moving passively and should be considered akinetic, irrespective of endocardial excursion. Segments with resting akinesis or dyskinesis are most likely composed of infarcted myocardium if the wall is thinned and dense, but in the absence of thinning are likely to consist of viable tissue. Indeed, hypokinetic segments are not identified as being infarcted, on the basis that residual contraction implies the presence of residual viability. Because the process of thinning and fibrosis takes some time after infarction, myocardium of normal thickness is commonly seen after recent or nontransmural infarction. Improvement of abnormal function in response to low doses of dobutamine (5 or 10 mcg/kg/min) or dipyridamole (0.28 or 0.56 mg/kg) suggests the presence of viable myocardium (Fig. 16-2). This finding is more reliable if the segment subsequently deteriorates, which indicates ischemia.

Figure 16-2 End-diastolic and end-systolic freeze-frame images illustrating LV enlargement on DSE in a patient with LV dysfunction and multivessel coronary artery disease.

There is a resting wall motion abnormality in the apex (large arrow), which is unchanged with stress. At peak stress, there is LV enlargement with reduction of systolic motion and thickening of the lateral (and to a lesser degree the septal) wall.

The global LV responses to dobutamine stress include a reduction of cavity size and an increase in cardiac output—mainly due to increased heart rate rather than stroke volume after intermediate dose (e.g., 20 mcg/kg/min), a point that is pertinent to the LV strain response (see later discussion). LV dilation implies multivessel or left main coronary artery disease (see Fig. 16-2), but this is less commonly seen with pharmacologic than with exercise stress, probably because of reduction of loading. Together with an extreme inotropic response, this afterload reduction may produce cavity obliteration (Fig. 16-3) and even outflow obstruction—which is not meaningful. Although the LV cavity obliteration response is favorable prognostically (presumably reflecting a low probability of multivessel disease),¹⁷ it may impair sensitivity both because of reduced transmural wall stress and because endocardial excursion is reduced and small areas of wall motion are unrecognized.¹⁸ Use of intravenous beta-blockade allows the heart rate to slow rapidly after stress, filling the LV cavity and revealing wall motion abnormalities that were unidentified at peak stress.¹⁹ A similar outcome can be obtained by poststress imaging.

Figure 16-3 End-systolic freeze-frame images of apical four-chamber views illustrating marked reduction in LV volume at peak stress, with close to cavity obliteration.

The resulting low transmural wall stress may prevent the induction of ischemia despite the presence of coronary artery disease.

The normal response to inotropic stress is to increase endocardial excursion, speed of contraction, and degree of myocardial thickening. A deterioration of function from rest, or after an initial enhancement of function, indicates ischemia (Fig. 16-4). Variants of overt deterioration include delayed contraction (“tardokinesis”) and reduced myocardial thickening. Caution should be applied in the assessment of periinfarct zones, which may fail to improve function with stress, or even appear dyskinetic if the infarct bulges due to tethering by the infarcted zone. Examination of wall thickening may assist in distinguishing periinfarct ischemia and tethering.

Figure 16-4 Apical two-chamber views illustrating the development of myocardial ischemia (reduced wall thickening, arrows) of the apex during DSE.

End-diastolic images are given on the left and systolic images on the right, with resting images above and peak dose below.

The evaluation of segments with abnormal resting function is more difficult. Akinetic or even dyskinesic segments may still be viable if they augment in response to either low-dose dipyridamole or dobutamine. Care must be taken to avoid misinterpretation based on differences in image planes, especially if the wall motion abnormality is localized. Deterioration of augmenting myocardium identifies ischemia, but in the absence of augmentation, a deterioration of function probably reflects increased loading rather than ischemia. Segments with resting hypokinesia often reflect nontransmural infarction, although some normal segments may be mildly hypokinetic, and it is important to be wary of overinterpretation, especially in the posterior wall. Analysis of myocardial deformation using 2D strain techniques has suggested that the pattern of impaired longitudinal function with preserved radial or rotational motion may be used to identify nontransmural infarction, as measured by gadolinium-enhanced MRI. Hypokinetic segments are also the most challenging for the identification of ischemia; those demonstrating a stress-induced improvement are classified as normal, and those showing a deterioration (compared with either rest or low-dose) are identified as ischemic. However, differentiation between degrees of hypokinesia may be difficult, even with side-by-side cineloop analysis. Some caution needs to be applied in the interpretation of regional variations in the degree of hyperkinesis, as these may occur in normal patients. There is a risk of overinterpretation of hypokinetic regions that fail to improve function in response to stress, even if adjacent segments mount a hyperkinetic response. A decision to characterize these as ischemic should be made in the context of the rest of the study.

The greatest limitations of the current application of stress echocardiography are concerns related to subjectivity and reproducibility. Although single-center studies have suggested that the interobserver variation in interpretation is small, interinstitution variability (although similar to that of other imaging techniques) is significant.²⁰ Interinstitution variability is particularly a problem in studies of poor image quality and in patients with mild ischemia. This discordance has been progressively reduced by definition of standard reading criteria²¹ and the adoption of harmonic imaging.²² The following reading guidelines are useful for controlling variation: Minor degrees of hypokinesia are not identified as ischemia (especially if only apparent at peak and not at poststress readings); focal abnormalities that do not follow angiographic territories are ignored; abnormalities are corroborated whenever possible with another view; basal inferior and septal segments are not identified as abnormal in the absence of a neighboring abnormal segment; studies are read by multiple observers whenever possible; and reading is blinded to all other data.

Finally, a standard sequence is of value in the interpretation of stress echocardiograms. We first review the resting data or previous transthoracic echocardiography (TTE) for non–wall-motion data that may color our interpretation, including M-mode and Doppler components. On the digital images, we first check that images are triggered correctly and that the prestress, peak stress, and poststress views are comparable. We then briefly review all of the side-by-side displays to see if there are new wall motion abnormalities or obvious changes in cavity size (suggesting multivessel disease) or cavity shape. Segmental analysis is carried out by careful comparison of regional function in each of the 16 segments, comparing the same site at rest and at stress. Both wall motion and thickening are compared, using both cineloop and frame-by-frame review of the digital images. Freezing the images and stepping through one frame at a time is invaluable—delayed contraction is a hallmark of ischemic tissue that is not apparent to the unaided eye, but is often recognizable when images are reviewed frame by frame. The reader should think twice about identifying resting- or stress-induced wall motion abnormalities in segments that move rapidly and smoothly in early systole. Focusing on the first part of systole may minimize the contribution of rotational or translational movement, and assessing the timing of contraction may also avoid false positive interpretations provoked by early relaxation (Fig. 16-5). The ability to save multiple cycles in each view has reduced the need to review continuous capture stress images, but these remain of value for nonstandard views and to check on uncertainties arising from the digitized images. The site, extent (number of abnormal segments), severity (segmental wall motion score), and time of onset and offset of ischemia, as well as the effect of ischemia on global LV function, should be recorded.

Figure 16-5 Apical four-chamber views illustrating the phenomenon of early relaxation.

A, Homogeneous contraction with reduction of apical cavity volume. B, Apical shape change after end of systole (broad arrow on electrocardiogram).

Protocols for Administration of Sympathomimetic Agents

Dobutamine has been administered using various empiric regimens, but none is clearly superior to the others. The most widely used is an incremental administration from 5 to 40 mcg/kg/min in 2- or 3-minute stages.⁵ Variants include maximal doses of up to 50 mcg/kg/min; lower dose-rates administered over longer periods are able to attain hemodynamic effects similar to those achieved by the high-dose protocols. New accelerated dobutamine protocols that have been used to reduce the duration of the test appear to be safe²³ but may sacrifice the ability to identify a biphasic response. Whichever regimen is applied, a reasonable (i.e., 2- to 3-minute) period at peak heart rate is desirable, as ischemic wall motion abnormalities may take a short time to become apparent. If atropine is added to induce an increase in heart rate, the usual dose is 1 to 2 mg total in 0.25-mg increments.

Hemodynamic Responses to Sympathomimetics

Low doses of dobutamine enhance LV contractility, usually without the development of tachycardia. At doses greater than 20 mcg/kg/min, systolic blood pressure increases and heart rate augments to more than 100 beats per minute. Heart rate can be expected to increase to about 120 beats per minute in most patients, reflecting a increment of 40 to 50 beats per minute. In normotensive patients, systolic blood pressure usually increases to about 170 mm Hg (i.e., by 30 to 40 mm Hg)—less during dobutamine than during exercise. The systolic pressure response may be marked in hypertensive patients and blunted in patients with LV dysfunction or multivessel coronary disease. The peak rate-pressure product is usually about 20,000—less than with exercise,^24–29 which has important implications for the relative sensitivity of dobutamine and exercise echocardiography. Although the development of ischemia at lower dobutamine doses and cardiac workloads indicates the presence of more extensive coronary disease, there is too much overlap for the hemodynamic response to be a reliable predictor of one-, two-, or three-vessel disease. The hemodynamic response to dobutamine shows significant variability between patients. Beta blockade may attenuate the physiologic response, with a significantly lower heart rate response (usually about 100 beats per minute), and a lower double-product (to levels of around 14,000), although this may be avoided by use of atropine.

Side Effects of Stress Testing with Sympathomimetic Agents

Other than the development of myocardial ischemia, dose-limiting side effects generally reflect intense adrenergic stimulation. Consequently, dobutamine stress is contraindicated in patients with severe hypertension and serious arrhythmias. Serious side effects are rare during DSE, with death, myocardial infarction, or sustained tachyarrhythmias in about 3 per 1000.^8,30 Nonetheless, case reports of fatalities have been reported from ventricular fibrillation and cardiac rupture,³¹ and safety in patients at highest risk—those with severe LV dysfunction—has been described only in small populations.³² Nonetheless, considering that the sickest patients (those unable to exercise and with questions of myocardial viability) undergo the test, this safety profile is reasonable. This may reflect the detection of ischemia by online imaging, permitting termination before serious problems arise.

Less serious complications include palpitations (atrial and ventricular extra systoles), hypertension, anxiety (sometimes manifested as dyspnea or vagal reactions), tremor, and urinary urgency. Hypotension may arise from the vasodilator effect of high-dose dobutamine, the development of outflow tract obstruction, or the development of severe ischemia.³³ Unlike hypotension during exercise testing, it does not denote the presence of serious coronary disease or LV dysfunction. In particular, the finding of an LV outflow tract gradient does not appear to be prognostically meaningful. The frequency of these side effects has varied from 5%, if only serious, dose-limiting side effects are considered, to 82%, if all side effects are included. Variability also relates to the type of stress protocol, the incidence being lower if the test is terminated for attainment of a target heart rate or at detection of ischemia or if submaximal test responses are excluded.

Stress Protocols

Dipyridamole is administered into a large proximal arm vein to minimize local discomfort from this strongly alkaline compound. Various dipyridamole administration regimens have been used. For myocardial perfusion imaging, the most commonly administered dose is 0.56 mg/kg IV, but the sensitivity of dipyridamole echocardiography is optimal if 2 minutes of infusion are added if the initial response is negative and no major side effects have appeared. Because the time of onset of ischemia correlates with the severity of coronary disease and prognosis, images are recorded every 2 minutes from the conclusion of the first dose until 18 minutes from the start. Digital images are saved at rest, before the start of the second dose (8 minutes), after the second dose (12 minutes, which is the most common time for the onset of ischemia), and at 16 minutes. Aminophylline (in aliquots of 50 to 75 mg intravenously) is used to reverse the effects of dipyridamole if severe ischemia or side effects arise; the threshold for using this agent is influenced by the overall LV function and the clinical state of the patient.

Because exogenous adenosine is able to act directly, it rapidly achieves steady state, and its biologic effects are of rapid onset. A fixed dose schedule of 0.14 or 0.17 mg/kg/min or incremental protocols (3-minute stages starting at 0.10 mg/kg/min, increasing to 0.14 and 0.18 mg/kg/ minute) been used for echocardiographic studies.^34,35 The use of aminophylline is rarely required for side effects, as these resolve within 1 minute of stopping the infusion.

Hemodynamic Responses to Vasodilators

The mechanism of ischemia with of vasodilator agents is chiefly through coronary steal. There is a small contribution of increasing oxygen demand from tachycardia, which may be a response to angina and side effects rather than arising from the agents themselves. Similarly, blood pressure is usually little changed by these stressors, which may cause hypotension. The addition of atropine leads to an augmentation of heart rate and cardiac work,⁹ effectively combining reduced coronary supply with increased oxygen demand.

Side Effects of Vasodilators

Side effects during dipyridamole stress usually follow completion of the infusion, rarely preclude completion of the study, and usually resolve spontaneously. Minor side effects, including flushing and headache, occur in about two thirds of patients studied with high-dose dipyridamole. Severe or prolonged myocardial ischemia is infrequent but can be treated with nitrates or aminophylline. Serious side effects are very rare—probably less frequent than with dobutamine^8,36—but severe myocardial ischemia and infarction, bronchospasm, complete heart block, and even death have been reported. Dipyridamole stress is contraindicated with atrioventricular block and bronchospasm, although patients with chronic obstructive airway disease with no or minimal airway reactivity may undergo the test.

The side-effect profile of adenosine is similar to that of dipyridamole, and although the intensity and frequency of side effects with adenosine is greater, they are of shorter duration. Some form of side effect occurs in most patients undergoing adenosine stress.³⁷ In a high-dose protocol,³⁵ side effects prevented about one third of patients from achieving peak dose, a comparable frequency to that found with dobutamine. Because the effect of adenosine is very transient, cessation of the infusion is usually the only treatment required for side effects. The use of regadenoson minimizes the risk of bronchospasm and heart block, is convenient because of a single dose, and has the same coronary vasodilator effect as dipyridamole,³⁸ but regadenoson is suited to study of perfusion rather than wall motion responses.

Stress Protocols

The use of an implanted pacemaker to alter the heart rate during testing is often necessary to achieve target heart rate in the presence of atrioventricular block, even if pharmacologic stress is being used. Ventricular stimulation produces dyssynchronous contraction, but interpretable images are obtainable if image quality is sufficient to evaluate thickening, and atrial pacing poses no problems for interpretation.³⁹ The test endpoints are the same as those for other nonexercise stressors; in the absence of these endpoints, pacing at peak heart rate is continued for 3 minutes. No protocol has been uniformly accepted. We use pacing in combination with dobutamine in order to obtain the inotropic response to stress, and therefore maintain a 3-minute incremental protocol when pacing is added, usually starting at 100 beats per minute.

Transesophageal pacing requires topical pharyngeal anesthesia and mild sedation and is rarely used. Use of a short protocol minimizes the risk of electrode movement and loss of capture. Atropine is often required to overcome atrioventricular block.

Hemodynamic Responses

The hemodynamic response to pacing is more controllable than with pharmacologic agents. Heart rates of 160 beats per minute are attainable, but systolic blood pressure is stable, giving a rate-pressure product of less than 20,000. Use of transesophageal pacing in an awake patient may itself provoke hemodynamic changes and hence ischemia, so that “resting” transesophageal echocardiographic images may not be truly acquired at rest.

Side Effects

Fewer side effects occur during transesophageal pacing than with pharmacologic stress. Esophageal discomfort, gagging, or nausea are uncommon with modern pacing electrodes. Angina may be provoked by stress but is usually self-limiting after cessation of pacing. Atrial flutter or fibrillation may also be precipitated. Esophageal injury is theoretically possible in response to high levels of stimulation over a prolonged period, but this has not been reported.