EDITORIAL COMMENT
Reduction in dipyridamole-induced single-photon emission computed tomography myocardial defect size by beta-blockers
Time to re-examine the patient preparation protocol for pharmacologic stress testing*
Myron C. Gerson, MD, FACC*,*
* University of Cincinnati, Division of Cardiology, Cincinnati, Ohio, USA
* Reprint requests and correspondence: Dr. Myron C. Gerson, Division of Cardiology, University of Cincinnati, 231 Albert Sabin Way #3057, P.O. Box 670542, Cincinnati, Ohio 45267-0542, USA.
Myron.Gerson{at}uc.edu
Over the past decade, pharmacologic coronary artery vasodilation in combination with single-photon emission computed tomography (SPECT) myocardial perfusion imaging has become an increasingly popular approach to the noninvasive detection of coronary artery disease. Numerous studies document comparable diagnostic accuracy of myocardial perfusion imaging with dynamic exercise and with pharmacologic coronary artery vasodilation (1). Single-photon emission computed tomography imaging after either dipyridamole or adenosine infusion has provided a valuable diagnostic tool in patients who are unable to exercise to target heart rate. In addition, pharmacologic coronary artery vasodilation should be substituted for dynamic exercise in the detection of coronary artery disease by SPECT imaging in patients with left bundle branch block or an implanted electronic pacemaker. In these patients, exercise-induced tachycardia can result in SPECT defects in the absence of coronary artery stenosis. At times pharmacologic stress has been substituted for dynamic exercise in patients receiving beta-adrenergic blockers because a beta-blocker might prevent the patient from reaching the target heart rate with exercise and interfere with the induction of myocardial ischemia (2). However, Sharir et al. (3) have cautioned that the continuation of antianginal drugs at the time of dipyridamole SPECT myocardial imaging could substantially reduce diagnostic sensitivity for the detection of single vessel coronary disease.
The current report by Taillefer et al. (4) in this issue of the Journal focuses specifically on the impact of beta-blockers on the diagnostic sensitivity of SPECT myocardial perfusion imaging with dipyridamole infusion. The authors completed a prospective, double-blind study of 21 patients with catheterization-proven coronary artery disease. The patients were randomly assigned to dipyridamole perfusion imaging on separate days with placebo, low-dose metoprolol (up to 10 mg intravenously), or high-dose metoprolol (up to 20 mg intravenously). By qualitative interpretation, the sensitivity of dipyridamole perfusion imaging for detection of individual coronary artery stenoses was 69% with placebo versus 52% with either low-dose or high-dose metoprolol (p = 0.039). The quantitative summed stress score was larger after placebo (11.5 ± 10.4) than low-dose (8.4 ± 9.2) or high-dose (9.1 ± 10.8) metoprolol (both p < 0.005). The authors conclude that the presence and severity of ischemic coronary artery disease may be underestimated in patients receiving beta-blocker therapy while undergoing dipyridamole stress myocardial perfusion imaging.
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What is the mechanism by which a beta-blocker might interfere with the production of perfusion defects in response to dipyridamole infusion?
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One theoretic possibility is that the beta-blocker could prevent an increase in myocardial oxygen demand by preventing the modest reflex tachycardia that often occurs with dipyridamole infusion. Although heart rate did increase significantly in placebo-treated patients with dipyridamole infusion in the Taillefer et al. (4) study, systolic and diastolic blood pressure fell significantly so that the rate-pressure product remained unchanged. This suggests that dipyridamole infusion did not produce perfusion defects under placebo conditions by increasing myocardial oxygen consumption and inducing ischemia.
The activation of beta-adrenergic receptors by catecholamines induces coronary artery vasodilation, increasing myocardial oxygen supply. Under baseline conditions, beta-blockade produces coronary artery vasoconstriction (5), possibly by leaving alpha-adrenergic activity unopposed. Under conditions of dipyridamole-induced coronary artery vasodilation, however, it has been demonstrated that metoprolol results in a reduction in coronary vascular resistance and an increase in coronary blood flow (6,7). Because a beta1-blocker would not directly dilate coronary arteries, it is likely that the observed reduction in coronary vascular resistance and increase in coronary blood flow is an indirect result of negative inotropic, negative chronotropic and, possibly, anti-ischemic effects.
Beller et al. (8) showed that in a setting of severe single-vessel coronary artery stenosis, dipyridamole infusion induces the coronary steal phenomenon by reducing post-stenotic subendocardial blood flow while maintaining or increasing post-stenotic subepicardial flow. In contrast, metoprolol can increase subendocardial blood flow to the post-stenotic myocardium in the presence of dipyridamole, resulting in improved regional wall thickening (5). This may result from reduced myocardial compression of intramyocardial subendocardial vessels through the negative inotropic effect of the beta-blocker. Beta-blockers may also help maintain intramyocardial coronary collateral flow by a similar mechanism, and this may avert the coronary steal phenomenon otherwise induced by dipyridamole. Additionally, beta-blockers may reduce ischemia by slowing the heart rate, thereby facilitating diastolic coronary flow.
Indirect support for the postulate that beta-blockade ameliorates maldistribution of blood flow induced by dipyridamole infusion comes from a dipyridamole echocardiographic study reported by Lattanzi et al. (9). Patients were tested with and without antianginal drugs, including propranolol in 27 patients. The sensitivity of dipyridamole echocardiography fell from 91% off antianginal therapy to 65% on therapy (p < 0.01). Dipyridamole echocardiography depends upon maldistribution of myocardial blood flow away from the subendocardium to induce regional wall motion abnormality, an effect that was prevented by antianginal treatment. It appears that beta-blockers, by averting this maldistribution of myocardial blood flow, can prevent detection of coronary artery stenosis during pharmacologic myocardial perfusion imaging with dipyridamole.
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What are the limitations of the Taillefer et al. (4) study?
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The study is small—21 patients completed the study protocol. This may well have prevented the identification of a statistically significant effect of beta-blockade on per-patient sensitivity for the detection of coronary disease with dipyridamole infusion. Study size did not prevent statistically significant reductions in quantitative perfusion defect size with metoprolol. Study design did not include patients in whom coronary disease was absent; therefore, the effects of beta-blockers on test specificity, normalcy rate, and overall accuracy are unclear. The study was performed with acute intravenous rather than chronic oral beta-blocker administration and thereby differs from the usual clinical scenario encountered in patients presenting for dipyridamole myocardial perfusion imaging. Furthermore, the results obtained with the beta1-selective blocker, metoprolol, may not be the same for treatment with nonselective beta-blockers, such as propranolol or carvedilol.
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What then are the clinical implications of the findings reported by Taillefer et al. (4)?
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Several studies have suggested that antianginal drugs interfere with detection of coronary artery disease with pharmacologic coronary artery vasodilation (3,10). Taillefer et al. (4) now present data focusing specifically on the interference of metoprolol with detection of coronary disease with dipyridamole myocardial perfusion testing. In patients referred for dipyridamole myocardial perfusion imaging for the purpose of determining the presence or extent of coronary disease, strong consideration should be given to withholding beta-blockers for four to five half-lives (e.g., 36 to 48 h) before testing. When the purpose of testing is to assess the clinical effectiveness of antianginal treatment, the beta-blocker should be continued. The decision to withhold beta-blockers for diagnostic testing must be considered carefully for each individual patient. Although small, there is a finite risk of life-threatening complications, including severe hypertension or an unstable coronary syndrome with beta-blocker withdrawal (11–14). Therefore, withholding beta-blockers for diagnostic testing may not be appropriate in high-risk patients. When beta-blockers are withheld for 36 to 48 h before diagnostic testing, the patient should be advised of the importance of promptly seeking medical care if symptoms of ischemia appear or escalate. New clinical studies are needed to determine more precisely the duration that beta-blockers, and other antianginal drugs should be withheld to avoid compromising the sensitivity of myocardial perfusion imaging with pharmacologic stress. Finally, because dipyridamole acts by preventing the inactivation of adenosine by adenosine deaminase and by preventing adenosine reuptake (15), it is likely that beta-blockers will interfere with detection of coronary disease with adenosine as well as with dipyridamole perfusion imaging. Further studies will be needed to confirm the effects of beta-blockers on dipyridamole perfusion imaging and to determine whether the sensitivity of adenosine perfusion imaging is compromised similarly.
In conclusion, the new data presented by Taillefer et al. (4) suggest that beta-blockers should be withheld temporarily before dipyridamole infusion for detection of coronary artery disease by myocardial perfusion imaging. The decision to withhold beta-blockers for diagnostic testing should be carefully considered on a case-by-case basis.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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- Varma SK, Watson DD, Beller GA. Quantitative comparison of thallium-201 scintigraphy after exercise and dipyridamole in coronary artery disease. Am J Cardiol. 1989;64:871–877[CrossRef][Medline]
- Beller GA. Dipyridamole: thallium-201 scintigraphy: an excellent alternative to exercise scintigraphy. J Am Coll Cardiol. 1989;14:1642–1644[Medline]
- Sharir T, Rabinowitz B, Livschitz S, et al. Underestimation of extent and severity of coronary artery disease by dipyridamole stress thallium-201 single-photon emission computed tomographic myocardial perfusion imaging in patients taking antianginal drugs. J Am Coll Cardiol. 1998;31:1540–1546[Abstract/Free Full Text]
- Taillefer R, Ahlberg AW, Masood Y, et al. Acute beta-blockade reduces the extent and severity of myocardial perfusion defects with dipyridamole Tc-99m sestamibi SPECT imaging. J Am Coll Cardiol 2003;42:1475–83
- Heusch G, Guth BD. Neurogenic regulation of coronary vasomotor tone. Eur Heart J. 1989;10(Suppl F):6–14
- Billinger M, Seiler C, Fleisch M, Eberli FR, Meier B, Hess OM. Do beta-adrenergic blocking agents increase coronary flow reserve? J Am Coll Cardiol. 2001;38:1866–1871[Abstract/Free Full Text]
- Bottcher M, Czernin J, Sun K, Phelps ME, Schelbert HR. Effect of beta1-adrenergic receptor blockade on myocardial blood flow and vasodilatory capacity. J Nucl Med. 1997;38:442–446[Abstract/Free Full Text]
- Beller GA, Holzgrefe HH, Watson DD. Effects of dipyridamole-induced vasodilation on myocardial uptake and clearance kinetics of thallium-201. Circulation. 1983;68:1328–1338[Abstract/Free Full Text]
- Lattanzi F, Picano E, Bolognese L, et al. Inhibition of dipyridamole-induced ischemia by antianginal therapy in humans. Correlation with exercise electrocardiography. Circulation. 1991;83:1256–1262[Abstract/Free Full Text]
- Kubota I, Ikeda K, Igarashi H, et al. Inhibition of dipyridamole-induced myocardial ischemia by diltiazem in patients with coronary artery disease. J Cardiovasc Pharmacol. 1987;9:363–367[Medline]
- Miller RR, Olson HG, Amsterdam EA, Mason DT. Propranolol-withdrawal rebound phenomenon. Exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med. 1975;293:416–418[Abstract]
- Alderman EL, Coltart DJ, Wettach GE, Harrison DC. Coronary artery syndromes after sudden propranolol withdrawal. Ann Intern Med. 1974;81:625–627[Medline]
- Lindenfeld J, Crawford MH, O'Rourke RA, Levine SP, Montiel MM, Horwitz LD. Adrenergic responsiveness after abrupt propranolol withdrawal in normal subjects and in patients with angina pectoris. Circulation. 1980;62:704–711[Abstract/Free Full Text]
- Myers MG, Wisenberg G. Sudden withdrawal of propranolol in patients with angina pectoris. Chest. 1977;71:24–26
- Knabb RM, Gidday JM, Ely SW, Rubio R, Berne RM. Effects of dipyridamole on myocardial adenosine and active hyperemia. Am J Physiol. 1984;247:H804–810[Medline]
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