Stress Echocardiography from 1979 to Present

Early Feasibility and Validation 

The initial reports of stress echocardiography were largely feasibility studies. It should be recognized that during the early days of stress echocardiography, 2D echocardiographic imaging was limited to 30-degree scanners with limited gray-scale resolution and remarkably low frame rates. This, combined with the challenges of imaging a heart during exercise, presented formidable obstacles. Nevertheless, several pioneers, including investigators in the Indiana University Echocardiography laboratory (Indianapolis, IN), pursued the objective of 2D echocardiographic imaging during stress with supine bicycle exercise (Figure). In a 1979 landmark article, Wann et al1 demonstrated the feasibility of identifying exercise-induced wall-motion abnormalities with 2D echocardiography and their resolution after successful coronary artery bypass surgery.

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Figure. Early two-dimensional stress echocardiogram using 30-degree scanner. Rest and stress images demonstrate apical dyskinesis at time of bicycle exercise (left) and resolution of exercise-induced ischemia after successful coronary artery bypass surgery (right). Reprinted from initial Indiana University article describing the clinical feasibility of exercise echocardiography.1

One of the first proposed solutions to the technical challenges of exercise echocardiography was to record the echocardiographic images immediately after treadmill exercise. This had the advantage of allowing exercise with a format more familiar than bicycle stress, while continuing to use protocols for ECG analysis that were of proven diagnostic accuracy. Thus, the echocardiographic imaging became an add-on to a standard treadmill exercise test, which was the accepted and traditional form of evaluating patients for known or suggested CAD. The initial studies were performed using standard methodology for recording of 2D echocardiograms on videotape allowing for sequential but not side-by-side evaluation of LV wall motion from videotaped images.2

Stress echocardiography languished for several years after these early reports of feasibility because of the cumbersome nature of acquiring exercise or postexercise imaging and the inability to compare rest and stress images in a side-by-side format for detection of subtle abnormalities. It was not until the mid-1980s, when early offline digital acquisition systems became available, that this type of comparison became feasible. These systems allowed capture of individual echocardiographic loops, which then could be edited to remove cycles that had marked translational motion or respiratory artifact. These were then played back as a continuous loop allowing for a more reliable evaluation of myocardial thickening and wall-motion abnormalities. Side-by-side display of rest and poststress images became available shortly afterward.

One of the early studies3 using digital methodology for evaluation of stress echocardiograms came from the echocardiography laboratory at Indiana University and was published in 1986. Intriguingly, the title of this study “Complementary Value of Two-dimensional Exercise Echocardiography to Routine Treadmill Exercise Testing” concluded that the echocardiographic portion would be additive and complementary to standard treadmill parameters when the ECG response was nondiagnostic. The advent of digital systems for acquisition and display of echocardiograms resulted in an exponential increase in interest in stress echocardiography as a competitor to the well-established radionuclide-based techniques. Today, after multiple, far more advanced, and larger studies than this modest study of 95 individuals, it has become apparent that the echocardiographic data are far more robust than those obtained by analysis of the ECG alone, independent of the nature of the ECG response.

The technical difficulty of acquiring images at the time of physical stress led to efforts at nonexercise forms of stress, such as handgrip exercise, which was demonstrated in early studies to be a feasible means of inducing ischemia. Subsequently, pharmacologic approaches to stress echocardiography were developed. In the United States, based in part on cost considerations, dobutamine rapidly became the favored agent as a combined inotropic and chronotropic mimicker of physical exercise. In Europe, vasodilator stress with dipyridamole became the favored agent for stress echocardiography. The bias toward dipyridamole in Europe was similarly based on cost considerations. At the time of the early studies, a dose of dipyridamole in the United States was approximately $130 per testing dose compared with the cost of well under $1 in Europe, whereas the cost of dobutamine in Europe was 4 to 10 times higher than that in the United States.

The search for an appropriate pharmacologic stressor in the United States included attempts at vasodilator stress and a pure heart rate increase with atropine. Other agents used in an effort to identify the ideal stressor included isoproterenol and dopamine. Dopamine was limited in its heart rate response and the downside of significant side effects if inadvertently extravasated from the intravenous space. Patient tolerance for isoproterenol infusion was poor. It rapidly became apparent that dobutamine was well tolerated by the overwhelming majority of patients and provided a relatively balanced inotropic and chronotropic response that mimicked the stages of physical exercise on a treadmill or bicycle ergometer.

Current Methodology 

During the past two and one-half decades, relatively standardized stress echocardiography protocols have evolved. All protocols have in common digital acquisition of echocardiographic images in multiple imaging planes at baseline, followed by acquisition of images at varying stages of cardiovascular stress and/or during the recovery period. Modern laboratories use digital acquisition methods that reside within the ultrasound platform itself rather than in stand-alone add-on digital “frame grabbers” that were used in the early years of stress echocardiography. Images can be displayed in a side-by-side format and the displayed images reconfigured to show either individual stages, such as rest and stress, or side by side to show individual views at each stage of stress. The latter configuration has the advantage of allowing a reader to simultaneously visualize wall motion at multiple levels of stress for comparison. This allows detection of more subtle wall-motion abnormalities.

Several methods for cardiovascular stress can be used with echocardiography (Table 1). The most commonly used techniques in the United States are exercise treadmill testing during which images are acquired at rest and immediately after treadmill exercise, and dobutamine stress echocardiography in which images are acquired at baseline and at each sequential stage of dobutamine infusion. The dobutamine doses used vary from laboratory to laboratory, but most commonly dobutamine is infused for 3-minute stages at doses of 10, 20, 30, and 40 μg/kg/min. Variations on dobutamine protocols include those designed specifically for detection of myocardial viability, in which case the doses may include a 5-μg/kg/min low dose and a peak dose at only 20 μg/kg/min. In many instances, dobutamine does not result in a sufficient heart rate response. Addition of atropine either at peak dose, or at intermediate stages, if dose responses are inadequate, will augment the heart rate response to more diagnostic levels.

Table 1. Stress echocardiography methods

	Exercise
	Posttreadmill exercise
	Supine or upright bicycle
	Handgrip
	Pharmacologic
	Dobutamine (±atropine)
	Dipyridamole (±atropine)
	Adenosine (±atropine)
	Combined dobutamine + dipyridamole
	Pharmacologic ± handgrip
	Other
	Transesophageal atrial pacing
	Transvenous pacing (temporary or permanent)
	Ergonovine⁎
	Hyperventilation⁎
	Cold pressor
	Mental stress

⁎ For provocation of coronary vasospasm.

Vasodilator stress, either with dipyridamole or adenosine or, more recently, adenosine triphosphate, has been used largely in European centers. Vasodilator stress results in flow mismatch in myocardial territories perfused by normal versus obstructed coronary arteries and subsequent development of an ischemic wall-motion abnormality. Animal data suggest that vasodilator stress is better suited to perfusion imaging than to wall-motion analysis. A combination of vasodilator stress with low-dose dobutamine to increase both oxygen demand and exacerbate flow discrepancies has also shown promise.

Other methods for stress have included isometric handgrip, which can be used alone or in conjunction with either dobutamine or vasodilator stress; cold pressor stress, which may unmask endothelial dysfunction; and agents such as ergonovine or forced hyperventilation designed to unmask coronary vasospasm. Irrespective of the stressor used, inducible wall-motion abnormalities remain the marker of underlying CAD. In addition to wall-motion analysis, Doppler interrogation can be used to track changes in valvular regurgitation or pulmonary artery pressures.

The mode of cardiovascular stress should be given significant consideration before using stress echocardiography. Depending on the indication, one form of stress may be far more appropriate and well validated than another. Table 2 outlines the preferred mode of cardiovascular stress depending on the indication. As a general rule, any patient capable of physical exercise should be tested with an exercise modality, as this preserves the integrity of the ECG response and provides valuable information regarding functional status. Performing echocardiography at the time of physical stress also allows links to be drawn among symptoms, cardiovascular workload, and wall-motion abnormalities. For other diagnoses, such as evaluation of pulmonary hypertension, bicycle exercise will be preferable to treadmill stress because it allows serial evaluation of tricuspid regurgitation jets for determination of right ventricular systolic pressure. One exception to the recommendation that all patients capable of exercise should exercise for stress may be in the evaluation of preoperative risk assessment and myocardial viability, where the overwhelming majority of the data validating stress echocardiography have been derived with pharmacologic (largely dobutamine) stress.

Table 2. Role of stress echocardiography in clinical decision making

		TME	Bike	DSE
	Chest pain evaluation	+	+	±
	Post-MI risk	+	+	+
	Viability	–	±	+
	Dyspnea/fatigue	+	+	–
	Preoperative risk assessment⁎	±	±	+
	Low gradient aortic stenosis	–	–	+
	Valvular disease	–	+	–
	Pulmonary hypertension	–	+	–

DSE, Dobutamine stress echocardiography; MI, myocardial infarction; TME, treadmill exercise; +, preferred technique; ±, alternate technique, if preferred method not feasible; –, not recommended, lack of data to support use.

⁎ For noncardiac surgery.

Independent of the type of stress used, wall-motion analysis for detection and quantitation of ischemic abnormalities remains the same. There are several levels of complexity on which wall-motion analysis can be undertaken. The simplest is a qualitative eyeball assessment of normal versus varying grades of abnormalities such as hypokinesis, akinesis, or dyskinesis in general anatomic regions of the LV. At a second level, abnormalities can be matched to a standardized multisegment LV model (current American Society of Echocardiography recommendations are for 17 segments) and each segment assigned a hierarchal score, typically with 1 being normal, 2 being hypokinetic, 3 being akinetic, and 4 being dyskinetic. This score can than be tabulated as a score index and rest and stress scores can be compared. This provides a semiquantitative method for following the severity of wall-motion abnormalities. More advanced quantitative schemes include determination of LV volumes in diastole and systole from which stroke volume and ejection fraction can be calculated. The normal nonischemic response is for both diastolic and systolic volumes to decrease with cardiovascular stress. Addition of quantitative information regarding ventricular volume provides additive value with respect to accuracy and prognosis. Finally, there are a number of Doppler-based modalities that will track myocardial velocities with high resolution that are being used. These will be discussed subsequently.

Accuracy for Detection of CAD 

After the initial demonstration of feasibility, investigators began evaluating the accuracy of stress echocardiography for detecting CAD. One of the earlier studies was performed in 95 patients undergoing routine treadmill exercise testing, all of whom had defined coronary anatomy.3 This study demonstrated the superior ability of echocardiographic imaging to identify abnormalities indicative of CAD, which were not apparent on evaluation of the ECG response to exercise. Importantly, this study was one of the first to demonstrate that the exercise echocardiogram provided incremental information in patients who had nondiagnostic ECG responses. Early studies such as this were followed rapidly by larger series investigating the relative value of exercise echocardiography in patients with and without prior myocardial infarction and the ability to detect multivessel disease. Table 3, Table 4 outline a number of the studies designed to evaluate accuracy of CAD detection using both exercise and pharmacologic stress echocardiography.

Table 3. Selected studies outlining the accuracy of exercise echocardiography

	Study	Exercise	N =	Sensitivity % All	Sensitivity SVD	Sensitivity MVD	Specificity %	PPV %	NPV %	Overall Accuracy %
	Armstrong et al4	TME	123	88	81	93	86	97	61	88
	Crouse et al5	TME	228	97	92	100	64	90	87	89
	Marwick et al6	TME	150	84	79	96	86	95	63	85
	Quinones et al7	TME	112	74	59	89	88	96	51	78
	Hecht et al8	SBE	180	93	84	100	86	95	79	91
	Roger et al9	TME	150	91	–	–	–	–	–	–
	Beleslin et al10	TME	136	88	88	91	82	97	50	88
	Roger et al11	TME	127	88	–	–	72	93	60	–
	Marwick et al12	TME	80	75	85	81	71	91	81
	Marwick et al13	TME	147	71	63	80	91	85	81	82
	Luotolahti et al14	UBE	118	94	94	93	70	97	50	92
	Roger et al15	TME	340	78	–	–	41	79	40	69

MVD, Multivessel disease; NPV, negative predictive value; PPV, positive predictive value; SBE, supine bicycle exercise; SVD, single-vessel disease; TME, treadmill exercise; UBE, upright bicycle exercise.

Table 4. Selected studies outlining the accuracy of dobutamine echocardiography

	Study	N =	Sensitivity %	Sensitivity SVD	Sensitivity MVD	Specificity %	PPV %	NPV %	Overall Accuracy %
	Segar et al16	88	95	–	–	82	94	86	92
	Marcovitz et al17	141	96	95	98	66	91	84	89
	McNeill et al18	80	70	–	–	88	89	67	78
	Marwick et al19	217	72	66	77	83	89	61	76
	Previtali et al20	80	79	63	91	83	92	61	80
	Takeuchi et al21	120	85	73	97	93	95	80	88

MVD, Multivessel disease; NPV, negative predictive value; PPV, positive predictive value; SVD, single-vessel disease.

The majority of studies have all suggested higher sensitivity for detecting patients with multivessel disease compared with those with single-vessel disease. It should be noted that these studies demonstrated higher sensitivity for detection of patients with multivessel disease, but all coronary lesions were not necessarily identified. A limitation of any symptom-limited stress test is that it may be discontinued at the onset of ischemia in the most critical coronary territory, therefore, not progressing to the point of unmasking less severe stenoses. Direct comparisons of different exercise modalities suggested that exercise testing with bicycle testing, which allows imaging at peak exercise, increases the sensitivity for detection of all coronary stenoses in patients with multivessel disease.22

Studies of accuracy have used different thresholds of coronary stenoses as relevant, typically greater than 50% or greater than 70% luminal narrowing on coronary angiography. As should be obvious from our understanding of coronary physiology, studies using a threshold of 70% stenosis for clinical relevance will have a higher sensitivity but lower specificity for detecting coronary disease.

Stress echocardiography has been compared, both directly and indirectly, with competing technologies such as radionuclide perfusion imaging regarding its accuracy for identifying patients with CAD. Most studies have demonstrated similar accuracies, typically with a slightly higher sensitivity for radionuclide-based perfusion imaging techniques and a higher specificity for echocardiographic imaging.23

Assessing Prognosis with Stress Echocardiography 

As stress echocardiography was validated as an accurate means of detecting obstructive CAD, attention turned to the prognostic relevance of positive and negative stress echocardiographic results. The early prognostic studies overlap significantly with many of the accuracy studies. One such study came from the Indiana University laboratory and involved 148 patients with a normal exercise echocardiogram finding. This was one of the first observations that a normal exercise stress echocardiogram result conferred a benign prognosis during a follow-up averaging 28.4 months. Cardiac events occurred in only 6 patients, all of whom exercised to submaximal levels. This study was the first to demonstrate an excellent intermediate-term prognosis in patients with a normal stress echocardiogram finding.24 Subsequently, numerous investigators evaluated the prognostic relevance of both positive and negative exercise echocardiogram results both in the general population and in specific patient subsets. A particularly large prognostic study of exercise echocardiography involved 5798 patients reported from the Mayo Clinic, Rochester, Minn, that compared the prognostic implications of exercise echocardiography in male and female patients followed up during 3.2 years. These authors demonstrated a slightly higher event rate in men than in women but a statistically significant correlation between wall-motion score index at stress and the likelihood of adverse outcomes during follow-up.25

The prognostic implications of a normal exercise echocardiogram and myocardial perfusion study were compared in a meta-analysis of available studies26 published between 1990 and 2005. This combined analysis suggested a negative predictive value for the hard end points of myocardial infarction and cardiac death of 98.8% for myocardial perfusion imaging and 98.4% for echocardiographic imaging during a follow-up of 36 and 33 months, respectively. This analysis also demonstrated equivalent prognostic power for male and female sex.

The prognostic implications of normal and abnormal dobutamine stress echocardiograms have also been extensively evaluated. One of the larger studies to do so was a report from the Cleveland Clinic Foundation, Cleveland, Ohio, and Indiana University of outcomes in 3156 patients who had undergone dobutamine stress echocardiography.27 The average age of patients was 63 ± 12 years, 1801 were male, and patients were followed up for an average of 3.8 years. This large study clearly demonstrated an incrementally worsened prognosis in patients with varying dobutamine echocardiographic abnormalities. After a normal dobutamine echocardiogram result, cardiac mortality was only 1% per year for the first 4 years of follow-up with incrementally greater annual mortality in the presence of ischemia, scar, or a combination of the two. This study also demonstrated that the key to survival was incrementally worsened by the presence of ischemia in 1, 2, or 3 coronary territories. Of note, this and other studies have demonstrated a hierarchy of adverse outcomes both for cardiac mortality and all-cause mortality.

Patients with diabetes mellitus are well known to have more advanced forms of CAD and a substantial cardiovascular mortality. In several studies, typically using pharmacologic stress echocardiography,28, 29, 30 patients with diabetes have specifically been evaluated. These studies have all demonstrated that an abnormal pharmacologic stress echocardiogram result confers a worsened prognosis compared with a normal stress echocardiogram finding and that outcomes are worse than in the nondiabetic population. Typically, these studies have demonstrated a 2- to 3-fold worse outcome for patients with diabetes compared with patients without diabetes for any level of stress abnormality.28, 29, 30

Stress echocardiography also has achieved substantial success in preoperative risk assessment before noncardiac surgery. The first study to suggest a role for dobutamine stress echocardiography as a predictor of cardiac events in major noncardiac surgery was published from Indiana University in 1992.31 This small study of 60 patients clearly demonstrated that an abnormal dobutamine echocardiogram finding conferred a substantially worsened prognosis with respect to perioperative ischemic events than was seen in patients with a nonischemic result. This study demonstrated an event rate of 4.6% in patients with a normal dobutamine echocardiogram result versus 29% in patients with an abnormal response. After this initial report, multiple centers around the world published similar and larger articles, all of which were uniform in demonstrating a significantly worse prognosis after an abnormal dobutamine echocardiogram result in patients undergoing noncardiac surgery. Two different meta-analyses have compared dobutamine stress echocardiography with stress radionuclide perfusion imaging for risk assessment before noncardiac surgery.32, 33 The first analysis, published in 1996, concluded that both dobutamine echocardiography and radionuclide perfusion had excellent and comparable accuracy for predicting cardiovascular events after noncardiac surgery.32 Of note, this analysis suggested a substantially higher odds ratio for adverse events with dobutamine stress echocardiography than was provided by radionuclide perfusion imaging. A second large review, published in 2003, compared studies of myocardial perfusion scintigraphy, dobutamine stress echocardiography, dipyridamole echocardiography, and exercise ECG for their prognostic ability to predict perioperative cardiac events in patients undergoing major cardiovascular surgery. This pooled analysis of more than 8000 patients suggested that the highest sensitivity (85%) was available from dobutamine stress echocardiography, which had a slight statistical advantage in accuracy compared with myocardial perfusion scintigraphy.33

Evaluation of Myocardial Viability 

The ability of dysfunctional myocardium to recover, either spontaneously or after revascularization, is referred to as viability. It suggests the potential for functional improvement and implies a state of either stunning or hibernation. Distinguishing viable from nonviable myocardium using dobutamine echocardiography is based on the premise that viable myocardium will augment in response to beta-adrenergic stimulation, and that the resulting changes in wall motion and wall thickening can be detected using 2D echocardiography. One of the earliest reports on this topic came from the Indiana University laboratory and was published in 1993.34 The study included a series of patients who presented with acute myocardial infarction and were subsequently treated with thrombolytic therapy. Low-dose dobutamine was used to distinguish patients who were destined to exhibit improvement in resting LV function from those with irreversible injury.

Subsequent reports confirmed and extended these early observations. It was recognized that a biphasic response (improvement at low-dose followed by deterioration at increasing doses of dobutamine) was most predictive of the potential for functional recovery.35 For predicting recovery of regional LV function, the sensitivity of dobutamine echocardiography ranges from 74% to 88%, whereas the specificity is between 73% and 90%. These results compare favorably with competing technologies, including radionuclide imaging.36 In most comparisons, dobutamine echocardiography is less sensitive, but more specific; that is, has slightly lower positive (but higher negative) predictive value.

The prognostic value of viability testing has also been examined using dobutamine stress. In a meta-analysis of more than 3000 patients (studied using either echocardiographic or nuclear imaging), Allman et al37 confirmed the important link between viability test results and subsequent management. Although based entirely on observational data, the weight of evidence suggests that when viability is present, revascularization improves outcome compared with medical therapy. However, when viability is absent, prognosis was similar regardless of treatment choice.

New Developments in Stress Echocardiography 

Conclusions 

Stress echocardiography has evolved during the past 25 years from the early days of demonstrating feasibility as a competitive tool in patients with coronary disease to a mainstay in the diagnostic armamentarium of clinical cardiologists. It provides diagnostic and prognostic information in a broad range of patient subsets and should play an integral role in the treatment of patients with suggested coronary disease, whether for diagnostic purposes or planning of further therapy. Newer technologies such as myocardial contrast for assessment of perfusion, detailed evaluation of myocardial mechanics with strain rate imaging, and 3D imaging show tremendous promise for even more sophisticated levels of data acquisition and analysis.