Pharmacologic Stress Echocardiography

Jagdish Shah M.D., Daniel Shindler M.D., John B. Kostis M.D.

Reproduced by permission from Practical Cardiology July 1991.

The use of a pharmacologic agent to stimulate the heart while an electrocardiogram and an echocardiogram are being recorded is relatively noninvasive. The procedure provides echocardiographic information about wall motion in addition to the standard electrocardiographic information. Wall motion abnormalities occur earlier during ischemia than electrocardiographic changes and precede angina. They therefore serve as an early mechanical marker of ischemia, which can be easily detected with echocardiography.

Advantages of Pharmacologic Stress Echocardiography

Because the patient is being constantly monitored with echocardiography as well as electrocardiography, it is immediately obvious when ischemia occurs. Once abnormal wall motion is observed, it is possible to stop further testing, avoiding more serious manifestations of myocardial ischemia. Orthostatic hypotension is less likely to develop than during exercise testing because the patient is lying down and does not have to be tilted or to walk or to pedal in place. The noncardiac side effects of the various pharmacologic agents are easily reversible. Furthermore, pharmacologic stress echocardiography yields higher quality images than does exercise echocardiography because there is no motion and no respiratory artifact. It also allows for reproducible Doppler sampling to detect changes in blood flow pattern induced by the pharmacologic stress.

Pharmacologic stress echocardiography is easier to perform than thallium-201 scintigraphy, and there is no need for the patient to return for rescanning. Transesophageal echocardiography provides a new window for ultrasonographic examination of the heart. This can provide improved resolution in patients in whom image quality is poor with transthoracic echocardiography.

Myocardial ischemia is a regional phenomenon. Regional wall motion analysis is, therefore, useful in assessing the location and extent of exercise or stress induced ischemia. This can be used in clinical decision-making (e.g., identifying the vessel requiring angioplasty).

Criteria for Test Interpretation

An increase in resting hypokinesia or new areas (not present prior to the infusion) of hypokinesia or akinesia are interpreted as positive. Any region that was akinetic at rest is not included in the analysis. Episodes of transient asynergy are also considered indicators of ischemia. On the electrocardiogram, ST-segment elevation is considered an indicator of transmural myocardial ischemia.

The information obtained from the study can also potentially be used to determine the degree of coronary reserve. When dipyridamole is used, the coronary reserve threshold is considered low if the changes noted herein are seen within three minutes, intermediate if they occur after three minutes, and high if they occur only with a high dose of dipyridamole.

Dipyridamole Echocardiography

Dipyridamole was first employed in the 1960s, when it was believed to benefit the heart by increasing coronary blood flow without increasing oxygen demand. It was found to be ineffective as an antianginal agent, however, and did not prevent changes in the electrocardiogram when compared with nitroglycerin. In 1968, it was found that a 20-minute infusion of 40 to 60 mg of dipyridamole resulted in an anginal attack. In 1974, a reduction in subendocardial blood flow in the presence of coronary artery obstruction with ST-segment depression and a fall in left ventricular dp/dt (ratio of change of ventricular pressure to change in time) were reported. In 1976, the dipyridamole echocardiography stress test was proposed for the diagnosis of coronary artery disease. Dipyridamole echocardiography was refined in the 1980s as the diagnostic capabilities of ultrasound equipment improved (1-4).

Intravenously administered dipyridamole produces marked coronary arteriolar vasodilation with less of a dilatory effect on peripheral arterioles. It prevents the cellular uptake of endogenous adenosine, thereby potentiating its vasodilator effect.

Various dosage regimens for intravenous dipyridamole have been described, ranging from 0.56 to 1.0 mg/kg of body weight in 10 minutes. A frequently used protocol is 0.56 mg/kg in four minutes. Another protocol that seems to increase sensitivity while reducing the incidence of side effects involves the infusion of 0.56 mg/kg over four minutes, then nothing for four minutes followed by 0.142 mg/kg/min for two minutes for a total of 0.84 mg/kg over a period of 10 minutes. The Food and Drug Administration (FDA) recommendation for intravenous dipyridamole thallium testing is 0.142 mg/kg/min (0.57 mg/kg total) infused over four minutes.

The sensitivities and specificities of two dipyridamole dosage schedules have been reported. The lower dose protocol using 0.56 mg/kg of intravenous dipyridamole has a sensitivity of 53 percent. When a higher dose of 0.84 mg/kg is used, the sensitivity increases to 74 percent with no increase in risk. The specificity of the high-dose dipyridamole test has been reported to be 100 percent with a feasibility of 100 percent. When echocardiography is combined with radionuclide angiography, the sensitivity further increases to 93 percent using an intermediate dose of 0.75 mg/kg of dipyridamole. The combination of echocardiography with radionuclide ventriculography may have a role when the echocardiographic images are not of good quality.

Safety data on 3,911 patients who underwent dipyridamole-thallium testing indicate that serious side effects are uncommon. Four myocardial infarctions, two fatal and two nonfatal, occurred; in three of these cases, the patients had a history of unstable angina. Noncardiac side effects (e.g., headaches, flushing, dizziness, nausea) were more frequent. Bronchospasm developed in six patients after intravenous dipyridamole (5). Most side effects subside without treatment, but aminophylline can be given if necessary (6).

Adenosine Echocardiography

Adenosine is a potent coronary vasodilator. It is a potent vasodilator in most vascular beds (except in renal afferent arterioles and hepatic veins where it produces vasoconstriction). Its mechanism of action has been postulated to be activation of purine receptors (cell surface A1 and A2 adenosine receptors). The exact mechanism by which adenosine receptor activation relaxes vascular smooth muscle is not known. There is evidence for both inihibition of the slow inward calcium current (reducing calcium uptake), and for activation of adenylate cyclase through A2 receptors in smooth muscle cells. This, in turn, relaxes the vascular smooth muscle and results in coronary arteriolar dilatation. The effects are the same as those of dipyridamole because the infusion of dipyridamole increases the adenosine level (by decreasing cellular uptake and deamination of adenosine). Five mechanisms have been defined in the consequent adenosine effect: passive coronary collapse, vertical steal, horizontal steal, systemic steal, and luxury perfusion (7). The outstanding characteristic of adenosine is its extremely short half-life--0.6 to 10 sec following bolus administration with complete elimination by 30 sec. Any side effects, therefore, are remarkably short-lived; this is an important advantage over the use of dipyridamole. It is also unnecessary to adjust doses in patients with underlying hepatic or renal disease.

Like dipyridamole, adenosine was initially used in conjunction with thallium imaging. The results of dipyridamole-thallium stress tests can be extrapolated to echocardiography. Verani et al (8) found that adenosine-thallium imaging had a sensitivity of 83 percent and a specificity of 94 percent for detection of coronary artery disease. Most false-negative results were obtained in patients with single-vessel disease.

The dosage used in adenosine-thallium studies was a drip at a rate of 50 micrograms/kg of body weight per minute, which was increased to 140 micrograms/kg/min or until wall-motion abnormalities were seen. If no abnormalities were observed, the dose was further increased to 180 micrograms/kg/min for a total duration of two to three minutes. In most patients, the dose of 140 micrograms/kg/min is sufficient because it causes near maximal coronary hyperemia (8).

Adenosine does not cause any long-lasting complications, and no life-threatening arrhythmias or sustained high-degree atrioventricular (AV) block has been reported. Minor side effects are quite common, however, with as many as 83 percent of patients reporting some symptoms. Chest, throat, or jaw pain was reported in 57 percent, headache in 35 percent, flushing in 29 percent, bradycardia in 8 percent, ischemic elecrocardiographic changes in 12 percent, and conduction abnormalities in the form of worsening first-degree AV block in 10 percent. Most of these side effects lasted for one or two minutes and were self-limited.

Dobutamine Echocardiography

Dobutamine stress echocardiography is another alternative to thillium-201 imaging and exercise electrocardiography for detection of coronary artery disease (9-11). Palac et al (12) studied 13 patients with coronary artery disease and three normal individuals. They administered 5 to 20 micrograms of dobutamine/kg/min and found a sensitivity of 77 percent and a specificity of 100 percent for detection of coronary artery disease. Seventy-seven percent of the patients with coronary artery disease and none of the normal individuals had new wall-motion abnormalities. They concluded that dobutamine may be useful for noninvasive assessment of wall-motion for the purpose of identifying patients with coronary artery disease.

Berthe et al (13) studied 30 patients five to 10 days after acute myocardial infarction using doses of 5 to 40 micrograms of dobutamine/kg/min. They reported a sensitivity of 85 percent and a specificity of 88 percent with an overall accuracy of 87 percent and a predictive value of 85 percent. They concluded that the test was safe and accurate and suggested that it may be useful for assessing the functional significance of coronary artery lesions even if they do not appear to be significant angiographically.

Mannering et a] (14) also used dobutamine echocardiography in postinfarction patients. They studied 50 patients three weeks after acute myocardial infarction using doses of dobutamine of 5 to 20 micrograms/kg/min and found 88 percent concordance with exercise electrocardiography. Beta blockers were stopped 48 hours before the test, but calcium antagonists, diuretics, and nitrates were continued. The investigators concluded that dobutamine echocardiography is economical and better than electrocardiographic exercise stress testing alone.

Lane et al (15) found dobutamine stress echocardiography useful in identifying patients at high or low risk of perioperative cardiac events. They studied 41 patients unable to exercise prior to major vascular or other surgery using 5 to 30 micrograms of dobutamine/kg/min.

Sawada et al (16) studied 134 patients with known or suspected coronary artery disease using 5 to 30 micrograms of dobutamine/kg/min. They concluded that dobutamine echocardiography is safe, accurate, and clinically useful for detecting coronary artery disease and for assessing its extent in patients with resting wall-motion abnormalities.

Cohen et a] (17) showed that compared with coronary angiography, dobutamine digital echocardiography had a sensitivity of 86 percent, specificity of 95 percent, and accuracy of 89 percent for detecting coronary artery disease. No major adverse reactions occurred, although some patients experienced transient chest pain, dyspnea, or asymptomatic, hemodynamically insignificant arrhythmias.

Conclusion

Pharmacologic stress echocardiography using such agents as dipyridamole, adenosine, and dobutamine provides an alternative to exercise stress testing, particularly in patients who are unable to perform an adequate exercise test because of physical handicaps or psychologic factors. The results of pharmacologic stress echocardiography are comparable to those of pharmacologic stress thallium scintigraphy, the test is easier to perform, and it is not necessary for the patient to return for scanning.

References

1 . Picano E et al J Am Coll Cardiol 8:848,1986
2. Picano E et al Am J Cardiol 58:235, 1986
3. Picano E et al Am J Cardiol 59: 59, 1987
4. Chambers CE et al J Am Coll Cardiol 12:37,1988
5. Ronhosky A et al Circulation 81:1205, 1990
6. Beer SD et al Am J Cardiol 67:180, 1991
7. Pelleg A, Porter RS Pharmacotherapy 10: 157, 1990
8. Verani MS et al Circulation 82:80, 1990
9. Mason JR et al Am Heart J 107:481, 1984
10. Freeman ML et al Clin Nucl Med 9:251, 1984
11. Hendrix GH et al Chest 92:1255,1987
12. Palac R et al J Am Coll Cardiot 1: 633,1983
13. Berthe C et al Am J Cardiol 58:1167, 1986
14. Mannering D et al J Am Coll Cardiol 9:121 A, 1987
15. Lane RT et al Circulation 80:11, 1989
16. Sawada SG et al Circulation 80:11, 1989
17. Cohen JL et al Am J Cardiol 67:1311, 1991

Back to E-chocardiography Home Page.