Portal de Periódicos da CAPES

A New Generation of Coronary Vasodilators in Stress Perfusion Imaging

2007; Elsevier BV; Volume: 99; Issue: 11 Linguagem: Inglês

10.1016/j.amjcard.2006.06.062

1879-1913

Ami E. Iskandrian,

Cardiac electrophysiology and arrhythmias

Although the cardiovascular effects of adenosine have been studied for almost 8 decades,1Iskandrian A.E. Verani M.S. Nuclear Cardiac Imaging: Principles and Applications. 3rd ed. Oxford University Press, New York2003: 164-189Google Scholar, 2Iskandrian A.S. Verani M.S. Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.J Nucl Cardiol. 1994; 1: 94-111Crossref PubMed Scopus (123) Google Scholar it was not until 1990 that the first report was published on the use of adenosine in stress myocardial perfusion imaging (MPI) with radiotracers.3Verani M.S. Mahmarian J.J. Hixson J.B. Boyce T.M. Staudacher R.A. Diagnosis of coronary artery disease with adenosine and thallium-201 scintigraphy in patients unable to exercise.Circulation. 1990; 82: 80-87Crossref PubMed Scopus (249) Google Scholar In 1995, adenosine (Adenoscan, Astellas, Deerfield, Illinois) was approved by the U.S. Food and Drug Administration for stress testing (adenosine, in the form of Adenocar (Astellas), was approved earlier in 1990 for the treatment of supraventricular tachycardia). At present, Adenoscan is used in approximately 60% of patients who undergo pharmacologic stress MPI, and vasodilator MPI is the fastest growing segment, accounting for approximately 40% of the roughly 8.5 million stress MPI studies performed annually in the United States alone. Adenosine is also used in other stress imaging modalities, such as 2-dimensional echocardiography and magnetic resonance imaging, and in cardiac catheterization laboratories (either intravenous or intracoronary) to study coronary hemodynamic assessment, where for practical purposes it has replaced intracoronary papaverine.1Iskandrian A.E. Verani M.S. Nuclear Cardiac Imaging: Principles and Applications. 3rd ed. Oxford University Press, New York2003: 164-189Google Scholar, 2Iskandrian A.S. Verani M.S. Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.J Nucl Cardiol. 1994; 1: 94-111Crossref PubMed Scopus (123) Google ScholarAdenosine is a naturally occurring ligand of 4 distinct subtypes of cell membrane G-protein coupled receptors.1Iskandrian A.E. Verani M.S. Nuclear Cardiac Imaging: Principles and Applications. 3rd ed. Oxford University Press, New York2003: 164-189Google Scholar, 2Iskandrian A.S. Verani M.S. Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.J Nucl Cardiol. 1994; 1: 94-111Crossref PubMed Scopus (123) Google Scholar, 4Shryock J.C. Snowdy S. Baraldi P.G. Cacciari B. Spalluto G. Monopoli A. Ongini E. Baker S.P. Belardinelli L. A2A-adenosine receptor reserve for coronary vasodilation.Circulation. 1998; 98: 711-718Crossref PubMed Scopus (155) Google Scholar, 5Biaggioni I. Killian T.J. Mosqueda-Garcia R. Robertson R.M. Robertson D. Adenosine increases sympathetic nerve traffic in humans.Circulation. 1991; 83: 1668-1675Crossref PubMed Scopus (175) Google Scholar, 6Belardinelli L. Shryock J.C. Snowdy S. Zhang Y. Monopoli A. Lozza G. Ongini E. Olsson R.A. Dennis D.M. The A2A adenosine receptor mediates coronary vasodilation.J Pharmacol Exp Ther. 1998; 284: 1066-1073PubMed Google Scholar The synthesis and elimination pathways are well described. The activation of A-2a receptors is responsible for coronary vasodilatation and an increase in myocardial blood flow (MBF). Unlike in exercise, the increase in MBF is not related to double product, and there is no indication that combining exercise with adenosine causes the further augmentation of MBF. A modest increase in heart rate is most likely due to direct sympathetic stimulation, not to the modest decrease in blood pressure.5Biaggioni I. Killian T.J. Mosqueda-Garcia R. Robertson R.M. Robertson D. Adenosine increases sympathetic nerve traffic in humans.Circulation. 1991; 83: 1668-1675Crossref PubMed Scopus (175) Google Scholar This sympathetic stimulation is also the result of A-2a receptor activation. Activation of the other receptor subtypes (A-2b, A-1, and A-3) is responsible for myriad consequences both desirable (such as cardiac protection) and undesirable (as side effects). These side effects include atrioventricular block, bronchospasm, nonangina chest pains, shortness of breadth, marked hypotension, flushing, and headaches. Furthermore, adenosine needs to be infused with an infusion pump over 4 to 6 minutes in a dose that is adjusted for body weight. Adenosine is popular principally because the degree of coronary hyperemia is predictable at or near maximum and because adenosine has an extremely short half-life of about 1 second.1Iskandrian A.E. Verani M.S. Nuclear Cardiac Imaging: Principles and Applications. 3rd ed. Oxford University Press, New York2003: 164-189Google Scholar, 2Iskandrian A.S. Verani M.S. Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.J Nucl Cardiol. 1994; 1: 94-111Crossref PubMed Scopus (123) Google Scholar, 7Cerqueira M.D. Verani M.S. Schwaiger M. Heo J. Iskandrian A.S. Safety profile of adenosine stress perfusion imaging: results from the Adenoscan Multicenter Trial Registry.J Am Coll Cardiol. 1994; 23: 384-389Abstract Full Text PDF PubMed Scopus (396) Google Scholar For any new stress agent to be considered an alternative to adenosine, it must meet the challenges of safety, tolerability, potency, short duration of action, and ease of administration.Selective A-2a AgonistsCurrently, there are 3 such agents in phase III clinical trials. These agents are hoped to have the desirable features but none of the side effects of adenosine, because that is what selectivity implies. These agents are regadenoson, binodenoson, and apadenoson. A forth agent (CGS21680) was studied only in an animal model and is not likely to enter clinical testing.8He Z.X. Cwajg E. Hwang W. Hartley C.J. Funk E. Michael L.H. Verani M.S. Myocardial blood flow and myocardial uptake of 201Tl and 99mTc-sestamibi during coronary vasodilation induced by CGS-21680, a selective adenosine A2A receptor agonist.Circulation. 2000; 102: 438-444Crossref PubMed Scopus (21) Google Scholar The 3 agonists share a common feature of selectivity, but they do differ in affinity, onset of action, duration of hyperemia, and dosing regimen (fixed or weight-adjusted dose). For example, regadenoson is given intravenously as a fixed-dose bolus, whereas binodenoson and apadenoson are given as weight-adjusted boluses.9Udelson J.E. Heller G.V. Wackers F.J.T. Chai A. Hinchman D. Coleman P.S. Dilsizian V. Dicarli M. Hachamovitch R. Johnson J.R. et al.Randomized controlled dose-ranging study of the selective adenosine A2a-adenosine receptor reserve for coronary vasodilatation.Circulation. 2004; 109: 457-464Crossref PubMed Scopus (71) Google Scholar, 10Hendel R.C. Bateman T.M. Cerqueira M.D. Iskandrian A.E. Leppo J.A. Blackburn B. Mahmarian J.J. Initial clinical experience with regadenoson, a novel selective A2A agonist for pharmacologic stress single-photon emission computed tomography myocardial perfusion imaging.J Am Coll Cardiol. 2005; 46: 2069-2075Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar A fixed dose is more attractive, because it decreases the chances of errors in dosing.The potency to augment MBF depends on the affinity of the agonist for the receptor, the density of the receptors in the coronary vessels, the intrinsic efficacy of the bound agonist to activate the receptors, and the receptor reserve.4Shryock J.C. Snowdy S. Baraldi P.G. Cacciari B. Spalluto G. Monopoli A. Ongini E. Baker S.P. Belardinelli L. A2A-adenosine receptor reserve for coronary vasodilation.Circulation. 1998; 98: 711-718Crossref PubMed Scopus (155) Google Scholar, 6Belardinelli L. Shryock J.C. Snowdy S. Zhang Y. Monopoli A. Lozza G. Ongini E. Olsson R.A. Dennis D.M. The A2A adenosine receptor mediates coronary vasodilation.J Pharmacol Exp Ther. 1998; 284: 1066-1073PubMed Google ScholarAffinity is defined as the ratio between the rate of drug dissociation or release from receptors and the rate of drug association or binding to the receptors. Affinity determines the duration of action. Agonists with high affinity have longer durations of action than drugs with low or moderate affinity. This difference in affinity could explain the longer duration of hyperemia of binodenoson than regadenoson and adenosine. Receptor subtype selectivity is concentration (or dose) dependent, which may explain in part why some non-A-2a side effects have been reported with all 3 “selective” agonists; alternatively, some of these side effects might be produced by A-2a activation and sympathetic stimulation.4Shryock J.C. Snowdy S. Baraldi P.G. Cacciari B. Spalluto G. Monopoli A. Ongini E. Baker S.P. Belardinelli L. A2A-adenosine receptor reserve for coronary vasodilation.Circulation. 1998; 98: 711-718Crossref PubMed Scopus (155) Google Scholar, 6Belardinelli L. Shryock J.C. Snowdy S. Zhang Y. Monopoli A. Lozza G. Ongini E. Olsson R.A. Dennis D.M. The A2A adenosine receptor mediates coronary vasodilation.J Pharmacol Exp Ther. 1998; 284: 1066-1073PubMed Google ScholarIn this issue of the American Journal of Cardiology, Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar present the coronary hemodynamic responses, measured with the Doppler catheter, in 133 patients after binodenoson administration. This was not a dose-response study; each patient at the 18 recruiting centers received 1 of the 5 prespecified doses (0.3, 0.5, or 1 μg/kg/min by infusion or 1.5 or 3 μg/kg as intravenous bolus). Although the 1.5 μg/kg bolus produced coronary hyperemia equivalent to that of intracoronary adenosine, and the duration of hyperemia was dose related, the range of augmentation of MBF, the time to peak effect, and the duration of hyperemia were quite variable and unpredictable (see Table 4 in Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). The predictability and consistency of these parameters are of paramount importance in stress MPI, especially if the stress agent is given as a bolus, because if the radiotracer is injected before peak hyperemia is achieved, ischemia detection could be compromised. This scenario is quite unlike that seen with adenosine, which is given as an infusion, with the tracer injected halfway through the infusion. These concerns notwithstanding, a phase II trial showed comparable MPI results between binodenoson and adenosine.9Udelson J.E. Heller G.V. Wackers F.J.T. Chai A. Hinchman D. Coleman P.S. Dilsizian V. Dicarli M. Hachamovitch R. Johnson J.R. et al.Randomized controlled dose-ranging study of the selective adenosine A2a-adenosine receptor reserve for coronary vasodilatation.Circulation. 2004; 109: 457-464Crossref PubMed Scopus (71) Google Scholar Patient selection, the severity of stenosis, and a small sample size might hide important differences between binodenoson and adenosine, and the results of a phase III trial would be of great importance. The curvilinear relation between peak MBF and tracer extraction, especially with technetium-99m-based tracers, might also lower the discordance rates between the 2 agents. The results of a phase III trial with 1 of the 3 selective A-2a agonists showed that regadenoson given as a fixed dose and a rapid bolus provided diagnostic information comparable with that obtained using a standard 6-minute adenosine infusion.Do we need a new and improved adenosine, which is 1 way of looking at these elective agonists? The answer is yes, provided they can offer results comparable with those achieved using adenosine; can be given as a bolus; have a duration of action that is long enough for tracer extraction to be complete but short enough to limit monitoring time, with its associated risk, side effects, and costs of monitoring; have similar or better side-effect and tolerability profiles as adenosine; and are priced competitively. Head-to-head comparisons between the 3 selective agonists are not yet available. More data are also needed on their use in special patient groups, such as those with bronchospastic lung disease, second-degree or higher atrioventricular block, and left bundle branch block in which excessive tachycardia might produce rate-related septal defects in the absence of lesions in the left anterior descending artery, and on their interaction with caffeine. A recent report showed that a low level of caffeine concentration did not alter the results obtained with adenosine MPI.12Zoghbi G.J. Htay T. Aqel R. Blackmon L. Heo J. Iskandrian A.E. Effect of caffeine on ischemia detection by adenosine single-photon emission computed tomography perfusion imaging.J Am Coll Cardiol. 2006; 47: 2296-2302Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Finally, the results in diabetic patients are of extreme interest, because adenosine affects insulin levels, and insulin and glucose levels affect peak MBF.13Srinivasan M. Herrero P. McGill J.B. Bennik J. Heere B. Lesniak D. Davila-Roman V.G. Gropler R.J. The effects of plasma insulin and glucose on myocardial blood flow in patients with type 1 diabetes mellitus.J Am Coll Cardiol. 2005; 46: 42-48Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar The report by Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar is much needed to better understand how to use this particular agonist in stress MPI. Although the cardiovascular effects of adenosine have been studied for almost 8 decades,1Iskandrian A.E. Verani M.S. Nuclear Cardiac Imaging: Principles and Applications. 3rd ed. Oxford University Press, New York2003: 164-189Google Scholar, 2Iskandrian A.S. Verani M.S. Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.J Nucl Cardiol. 1994; 1: 94-111Crossref PubMed Scopus (123) Google Scholar it was not until 1990 that the first report was published on the use of adenosine in stress myocardial perfusion imaging (MPI) with radiotracers.3Verani M.S. Mahmarian J.J. Hixson J.B. Boyce T.M. Staudacher R.A. Diagnosis of coronary artery disease with adenosine and thallium-201 scintigraphy in patients unable to exercise.Circulation. 1990; 82: 80-87Crossref PubMed Scopus (249) Google Scholar In 1995, adenosine (Adenoscan, Astellas, Deerfield, Illinois) was approved by the U.S. Food and Drug Administration for stress testing (adenosine, in the form of Adenocar (Astellas), was approved earlier in 1990 for the treatment of supraventricular tachycardia). At present, Adenoscan is used in approximately 60% of patients who undergo pharmacologic stress MPI, and vasodilator MPI is the fastest growing segment, accounting for approximately 40% of the roughly 8.5 million stress MPI studies performed annually in the United States alone. Adenosine is also used in other stress imaging modalities, such as 2-dimensional echocardiography and magnetic resonance imaging, and in cardiac catheterization laboratories (either intravenous or intracoronary) to study coronary hemodynamic assessment, where for practical purposes it has replaced intracoronary papaverine.1Iskandrian A.E. Verani M.S. Nuclear Cardiac Imaging: Principles and Applications. 3rd ed. Oxford University Press, New York2003: 164-189Google Scholar, 2Iskandrian A.S. Verani M.S. Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.J Nucl Cardiol. 1994; 1: 94-111Crossref PubMed Scopus (123) Google Scholar Adenosine is a naturally occurring ligand of 4 distinct subtypes of cell membrane G-protein coupled receptors.1Iskandrian A.E. Verani M.S. Nuclear Cardiac Imaging: Principles and Applications. 3rd ed. Oxford University Press, New York2003: 164-189Google Scholar, 2Iskandrian A.S. Verani M.S. Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.J Nucl Cardiol. 1994; 1: 94-111Crossref PubMed Scopus (123) Google Scholar, 4Shryock J.C. Snowdy S. Baraldi P.G. Cacciari B. Spalluto G. Monopoli A. Ongini E. Baker S.P. Belardinelli L. A2A-adenosine receptor reserve for coronary vasodilation.Circulation. 1998; 98: 711-718Crossref PubMed Scopus (155) Google Scholar, 5Biaggioni I. Killian T.J. Mosqueda-Garcia R. Robertson R.M. Robertson D. Adenosine increases sympathetic nerve traffic in humans.Circulation. 1991; 83: 1668-1675Crossref PubMed Scopus (175) Google Scholar, 6Belardinelli L. Shryock J.C. Snowdy S. Zhang Y. Monopoli A. Lozza G. Ongini E. Olsson R.A. Dennis D.M. The A2A adenosine receptor mediates coronary vasodilation.J Pharmacol Exp Ther. 1998; 284: 1066-1073PubMed Google Scholar The synthesis and elimination pathways are well described. The activation of A-2a receptors is responsible for coronary vasodilatation and an increase in myocardial blood flow (MBF). Unlike in exercise, the increase in MBF is not related to double product, and there is no indication that combining exercise with adenosine causes the further augmentation of MBF. A modest increase in heart rate is most likely due to direct sympathetic stimulation, not to the modest decrease in blood pressure.5Biaggioni I. Killian T.J. Mosqueda-Garcia R. Robertson R.M. Robertson D. Adenosine increases sympathetic nerve traffic in humans.Circulation. 1991; 83: 1668-1675Crossref PubMed Scopus (175) Google Scholar This sympathetic stimulation is also the result of A-2a receptor activation. Activation of the other receptor subtypes (A-2b, A-1, and A-3) is responsible for myriad consequences both desirable (such as cardiac protection) and undesirable (as side effects). These side effects include atrioventricular block, bronchospasm, nonangina chest pains, shortness of breadth, marked hypotension, flushing, and headaches. Furthermore, adenosine needs to be infused with an infusion pump over 4 to 6 minutes in a dose that is adjusted for body weight. Adenosine is popular principally because the degree of coronary hyperemia is predictable at or near maximum and because adenosine has an extremely short half-life of about 1 second.1Iskandrian A.E. Verani M.S. Nuclear Cardiac Imaging: Principles and Applications. 3rd ed. Oxford University Press, New York2003: 164-189Google Scholar, 2Iskandrian A.S. Verani M.S. Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease.J Nucl Cardiol. 1994; 1: 94-111Crossref PubMed Scopus (123) Google Scholar, 7Cerqueira M.D. Verani M.S. Schwaiger M. Heo J. Iskandrian A.S. Safety profile of adenosine stress perfusion imaging: results from the Adenoscan Multicenter Trial Registry.J Am Coll Cardiol. 1994; 23: 384-389Abstract Full Text PDF PubMed Scopus (396) Google Scholar For any new stress agent to be considered an alternative to adenosine, it must meet the challenges of safety, tolerability, potency, short duration of action, and ease of administration. Selective A-2a AgonistsCurrently, there are 3 such agents in phase III clinical trials. These agents are hoped to have the desirable features but none of the side effects of adenosine, because that is what selectivity implies. These agents are regadenoson, binodenoson, and apadenoson. A forth agent (CGS21680) was studied only in an animal model and is not likely to enter clinical testing.8He Z.X. Cwajg E. Hwang W. Hartley C.J. Funk E. Michael L.H. Verani M.S. Myocardial blood flow and myocardial uptake of 201Tl and 99mTc-sestamibi during coronary vasodilation induced by CGS-21680, a selective adenosine A2A receptor agonist.Circulation. 2000; 102: 438-444Crossref PubMed Scopus (21) Google Scholar The 3 agonists share a common feature of selectivity, but they do differ in affinity, onset of action, duration of hyperemia, and dosing regimen (fixed or weight-adjusted dose). For example, regadenoson is given intravenously as a fixed-dose bolus, whereas binodenoson and apadenoson are given as weight-adjusted boluses.9Udelson J.E. Heller G.V. Wackers F.J.T. Chai A. Hinchman D. Coleman P.S. Dilsizian V. Dicarli M. Hachamovitch R. Johnson J.R. et al.Randomized controlled dose-ranging study of the selective adenosine A2a-adenosine receptor reserve for coronary vasodilatation.Circulation. 2004; 109: 457-464Crossref PubMed Scopus (71) Google Scholar, 10Hendel R.C. Bateman T.M. Cerqueira M.D. Iskandrian A.E. Leppo J.A. Blackburn B. Mahmarian J.J. Initial clinical experience with regadenoson, a novel selective A2A agonist for pharmacologic stress single-photon emission computed tomography myocardial perfusion imaging.J Am Coll Cardiol. 2005; 46: 2069-2075Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar A fixed dose is more attractive, because it decreases the chances of errors in dosing.The potency to augment MBF depends on the affinity of the agonist for the receptor, the density of the receptors in the coronary vessels, the intrinsic efficacy of the bound agonist to activate the receptors, and the receptor reserve.4Shryock J.C. Snowdy S. Baraldi P.G. Cacciari B. Spalluto G. Monopoli A. Ongini E. Baker S.P. Belardinelli L. A2A-adenosine receptor reserve for coronary vasodilation.Circulation. 1998; 98: 711-718Crossref PubMed Scopus (155) Google Scholar, 6Belardinelli L. Shryock J.C. Snowdy S. Zhang Y. Monopoli A. Lozza G. Ongini E. Olsson R.A. Dennis D.M. The A2A adenosine receptor mediates coronary vasodilation.J Pharmacol Exp Ther. 1998; 284: 1066-1073PubMed Google ScholarAffinity is defined as the ratio between the rate of drug dissociation or release from receptors and the rate of drug association or binding to the receptors. Affinity determines the duration of action. Agonists with high affinity have longer durations of action than drugs with low or moderate affinity. This difference in affinity could explain the longer duration of hyperemia of binodenoson than regadenoson and adenosine. Receptor subtype selectivity is concentration (or dose) dependent, which may explain in part why some non-A-2a side effects have been reported with all 3 “selective” agonists; alternatively, some of these side effects might be produced by A-2a activation and sympathetic stimulation.4Shryock J.C. Snowdy S. Baraldi P.G. Cacciari B. Spalluto G. Monopoli A. Ongini E. Baker S.P. Belardinelli L. A2A-adenosine receptor reserve for coronary vasodilation.Circulation. 1998; 98: 711-718Crossref PubMed Scopus (155) Google Scholar, 6Belardinelli L. Shryock J.C. Snowdy S. Zhang Y. Monopoli A. Lozza G. Ongini E. Olsson R.A. Dennis D.M. The A2A adenosine receptor mediates coronary vasodilation.J Pharmacol Exp Ther. 1998; 284: 1066-1073PubMed Google ScholarIn this issue of the American Journal of Cardiology, Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar present the coronary hemodynamic responses, measured with the Doppler catheter, in 133 patients after binodenoson administration. This was not a dose-response study; each patient at the 18 recruiting centers received 1 of the 5 prespecified doses (0.3, 0.5, or 1 μg/kg/min by infusion or 1.5 or 3 μg/kg as intravenous bolus). Although the 1.5 μg/kg bolus produced coronary hyperemia equivalent to that of intracoronary adenosine, and the duration of hyperemia was dose related, the range of augmentation of MBF, the time to peak effect, and the duration of hyperemia were quite variable and unpredictable (see Table 4 in Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). The predictability and consistency of these parameters are of paramount importance in stress MPI, especially if the stress agent is given as a bolus, because if the radiotracer is injected before peak hyperemia is achieved, ischemia detection could be compromised. This scenario is quite unlike that seen with adenosine, which is given as an infusion, with the tracer injected halfway through the infusion. These concerns notwithstanding, a phase II trial showed comparable MPI results between binodenoson and adenosine.9Udelson J.E. Heller G.V. Wackers F.J.T. Chai A. Hinchman D. Coleman P.S. Dilsizian V. Dicarli M. Hachamovitch R. Johnson J.R. et al.Randomized controlled dose-ranging study of the selective adenosine A2a-adenosine receptor reserve for coronary vasodilatation.Circulation. 2004; 109: 457-464Crossref PubMed Scopus (71) Google Scholar Patient selection, the severity of stenosis, and a small sample size might hide important differences between binodenoson and adenosine, and the results of a phase III trial would be of great importance. The curvilinear relation between peak MBF and tracer extraction, especially with technetium-99m-based tracers, might also lower the discordance rates between the 2 agents. The results of a phase III trial with 1 of the 3 selective A-2a agonists showed that regadenoson given as a fixed dose and a rapid bolus provided diagnostic information comparable with that obtained using a standard 6-minute adenosine infusion.Do we need a new and improved adenosine, which is 1 way of looking at these elective agonists? The answer is yes, provided they can offer results comparable with those achieved using adenosine; can be given as a bolus; have a duration of action that is long enough for tracer extraction to be complete but short enough to limit monitoring time, with its associated risk, side effects, and costs of monitoring; have similar or better side-effect and tolerability profiles as adenosine; and are priced competitively. Head-to-head comparisons between the 3 selective agonists are not yet available. More data are also needed on their use in special patient groups, such as those with bronchospastic lung disease, second-degree or higher atrioventricular block, and left bundle branch block in which excessive tachycardia might produce rate-related septal defects in the absence of lesions in the left anterior descending artery, and on their interaction with caffeine. A recent report showed that a low level of caffeine concentration did not alter the results obtained with adenosine MPI.12Zoghbi G.J. Htay T. Aqel R. Blackmon L. Heo J. Iskandrian A.E. Effect of caffeine on ischemia detection by adenosine single-photon emission computed tomography perfusion imaging.J Am Coll Cardiol. 2006; 47: 2296-2302Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Finally, the results in diabetic patients are of extreme interest, because adenosine affects insulin levels, and insulin and glucose levels affect peak MBF.13Srinivasan M. Herrero P. McGill J.B. Bennik J. Heere B. Lesniak D. Davila-Roman V.G. Gropler R.J. The effects of plasma insulin and glucose on myocardial blood flow in patients with type 1 diabetes mellitus.J Am Coll Cardiol. 2005; 46: 42-48Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar The report by Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar is much needed to better understand how to use this particular agonist in stress MPI. Currently, there are 3 such agents in phase III clinical trials. These agents are hoped to have the desirable features but none of the side effects of adenosine, because that is what selectivity implies. These agents are regadenoson, binodenoson, and apadenoson. A forth agent (CGS21680) was studied only in an animal model and is not likely to enter clinical testing.8He Z.X. Cwajg E. Hwang W. Hartley C.J. Funk E. Michael L.H. Verani M.S. Myocardial blood flow and myocardial uptake of 201Tl and 99mTc-sestamibi during coronary vasodilation induced by CGS-21680, a selective adenosine A2A receptor agonist.Circulation. 2000; 102: 438-444Crossref PubMed Scopus (21) Google Scholar The 3 agonists share a common feature of selectivity, but they do differ in affinity, onset of action, duration of hyperemia, and dosing regimen (fixed or weight-adjusted dose). For example, regadenoson is given intravenously as a fixed-dose bolus, whereas binodenoson and apadenoson are given as weight-adjusted boluses.9Udelson J.E. Heller G.V. Wackers F.J.T. Chai A. Hinchman D. Coleman P.S. Dilsizian V. Dicarli M. Hachamovitch R. Johnson J.R. et al.Randomized controlled dose-ranging study of the selective adenosine A2a-adenosine receptor reserve for coronary vasodilatation.Circulation. 2004; 109: 457-464Crossref PubMed Scopus (71) Google Scholar, 10Hendel R.C. Bateman T.M. Cerqueira M.D. Iskandrian A.E. Leppo J.A. Blackburn B. Mahmarian J.J. Initial clinical experience with regadenoson, a novel selective A2A agonist for pharmacologic stress single-photon emission computed tomography myocardial perfusion imaging.J Am Coll Cardiol. 2005; 46: 2069-2075Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar A fixed dose is more attractive, because it decreases the chances of errors in dosing. The potency to augment MBF depends on the affinity of the agonist for the receptor, the density of the receptors in the coronary vessels, the intrinsic efficacy of the bound agonist to activate the receptors, and the receptor reserve.4Shryock J.C. Snowdy S. Baraldi P.G. Cacciari B. Spalluto G. Monopoli A. Ongini E. Baker S.P. Belardinelli L. A2A-adenosine receptor reserve for coronary vasodilation.Circulation. 1998; 98: 711-718Crossref PubMed Scopus (155) Google Scholar, 6Belardinelli L. Shryock J.C. Snowdy S. Zhang Y. Monopoli A. Lozza G. Ongini E. Olsson R.A. Dennis D.M. The A2A adenosine receptor mediates coronary vasodilation.J Pharmacol Exp Ther. 1998; 284: 1066-1073PubMed Google Scholar Affinity is defined as the ratio between the rate of drug dissociation or release from receptors and the rate of drug association or binding to the receptors. Affinity determines the duration of action. Agonists with high affinity have longer durations of action than drugs with low or moderate affinity. This difference in affinity could explain the longer duration of hyperemia of binodenoson than regadenoson and adenosine. Receptor subtype selectivity is concentration (or dose) dependent, which may explain in part why some non-A-2a side effects have been reported with all 3 “selective” agonists; alternatively, some of these side effects might be produced by A-2a activation and sympathetic stimulation.4Shryock J.C. Snowdy S. Baraldi P.G. Cacciari B. Spalluto G. Monopoli A. Ongini E. Baker S.P. Belardinelli L. A2A-adenosine receptor reserve for coronary vasodilation.Circulation. 1998; 98: 711-718Crossref PubMed Scopus (155) Google Scholar, 6Belardinelli L. Shryock J.C. Snowdy S. Zhang Y. Monopoli A. Lozza G. Ongini E. Olsson R.A. Dennis D.M. The A2A adenosine receptor mediates coronary vasodilation.J Pharmacol Exp Ther. 1998; 284: 1066-1073PubMed Google Scholar In this issue of the American Journal of Cardiology, Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar present the coronary hemodynamic responses, measured with the Doppler catheter, in 133 patients after binodenoson administration. This was not a dose-response study; each patient at the 18 recruiting centers received 1 of the 5 prespecified doses (0.3, 0.5, or 1 μg/kg/min by infusion or 1.5 or 3 μg/kg as intravenous bolus). Although the 1.5 μg/kg bolus produced coronary hyperemia equivalent to that of intracoronary adenosine, and the duration of hyperemia was dose related, the range of augmentation of MBF, the time to peak effect, and the duration of hyperemia were quite variable and unpredictable (see Table 4 in Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). The predictability and consistency of these parameters are of paramount importance in stress MPI, especially if the stress agent is given as a bolus, because if the radiotracer is injected before peak hyperemia is achieved, ischemia detection could be compromised. This scenario is quite unlike that seen with adenosine, which is given as an infusion, with the tracer injected halfway through the infusion. These concerns notwithstanding, a phase II trial showed comparable MPI results between binodenoson and adenosine.9Udelson J.E. Heller G.V. Wackers F.J.T. Chai A. Hinchman D. Coleman P.S. Dilsizian V. Dicarli M. Hachamovitch R. Johnson J.R. et al.Randomized controlled dose-ranging study of the selective adenosine A2a-adenosine receptor reserve for coronary vasodilatation.Circulation. 2004; 109: 457-464Crossref PubMed Scopus (71) Google Scholar Patient selection, the severity of stenosis, and a small sample size might hide important differences between binodenoson and adenosine, and the results of a phase III trial would be of great importance. The curvilinear relation between peak MBF and tracer extraction, especially with technetium-99m-based tracers, might also lower the discordance rates between the 2 agents. The results of a phase III trial with 1 of the 3 selective A-2a agonists showed that regadenoson given as a fixed dose and a rapid bolus provided diagnostic information comparable with that obtained using a standard 6-minute adenosine infusion. Do we need a new and improved adenosine, which is 1 way of looking at these elective agonists? The answer is yes, provided they can offer results comparable with those achieved using adenosine; can be given as a bolus; have a duration of action that is long enough for tracer extraction to be complete but short enough to limit monitoring time, with its associated risk, side effects, and costs of monitoring; have similar or better side-effect and tolerability profiles as adenosine; and are priced competitively. Head-to-head comparisons between the 3 selective agonists are not yet available. More data are also needed on their use in special patient groups, such as those with bronchospastic lung disease, second-degree or higher atrioventricular block, and left bundle branch block in which excessive tachycardia might produce rate-related septal defects in the absence of lesions in the left anterior descending artery, and on their interaction with caffeine. A recent report showed that a low level of caffeine concentration did not alter the results obtained with adenosine MPI.12Zoghbi G.J. Htay T. Aqel R. Blackmon L. Heo J. Iskandrian A.E. Effect of caffeine on ischemia detection by adenosine single-photon emission computed tomography perfusion imaging.J Am Coll Cardiol. 2006; 47: 2296-2302Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Finally, the results in diabetic patients are of extreme interest, because adenosine affects insulin levels, and insulin and glucose levels affect peak MBF.13Srinivasan M. Herrero P. McGill J.B. Bennik J. Heere B. Lesniak D. Davila-Roman V.G. Gropler R.J. The effects of plasma insulin and glucose on myocardial blood flow in patients with type 1 diabetes mellitus.J Am Coll Cardiol. 2005; 46: 42-48Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar The report by Hodgson et al11Hodgson J. McB. Dib N. Kern M.J. Bach R.G. Barrett R.J. Coronary circulation responses to binodenoson, a selective adenosine A2a receptor agonist.Am J Cardiol. 2007; 99: 1507-1512Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar is much needed to better understand how to use this particular agonist in stress MPI.