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Current Methods of Pharmacologic Stress Testing and the Potential Advantages of New Agents^*

Divisions of Cardiology and Nuclear Medicine, Departments of Medicine and Radiology, University of California San Francisco, San Francisco, California

View larger version (71K): [in this window] [in a new window]   FIGURE 1.  Shown are pathways of adenosine production transport, receptor activation, and metabolism. (Adapted with permission of (10).)

View larger version (57K): [in this window] [in a new window]   FIGURE 2.  Four adenosine receptor subtypes—A1, A2A, A2B, and A3—have been characterized and cloned. Stimulation of these receptors accounts for varied effects on electrical conduction, vasodilation, and bronchoconstriction. Illustrated are several adenosine receptor agonists and physiologic responses that result from stimulation of selective receptor subtypes. Shown also are inhibitors of 2 pathways. (Adapted with permission of (28).)

View larger version (18K): [in this window] [in a new window]   FIGURE 3.  Shown are chemical compositions for regadenoson and binodenoson, compared with adenosine. Also presented are parameters of affinity and potency along with demonstration of its functional selectivity for A2A receptors. Affinity relates to tightness of binding of agent to receptor and its resultant duration of action. Adenosine is a low-affinity agent that is quickly released. Higher affinity of new and more specific A2A agonists does not seemingly interfere with preferential aminophylline binding and its use as antidote.

View larger version (38K): [in this window] [in a new window]   FIGURE 4.  Shown diagrammatically are clinical infusion protocols recommended for regadenoson and binodenoson. These are designed on the basis of pharmacokinetics of the agents and their necessary interaction with the imaging agent.

View larger version (19K): [in this window] [in a new window]   FIGURE 5.  (A) Shown is time course of changes in coronary blood flow with regadenoson (solid curve) and adenosine (dashed curve). (Adapted with permission of (33).) (B) Shown above line for dogs are incremental changes in coronary flow (QCX) noted with serial increases in binodenoson dosage, compared with adenosine dosage. Decremental changes in mean arterial pressure (MAP) are plotted below line. (Adapted with permission of (34).) (C) Shown is time course of changes in coronary conductance, coronary blood flow normalized for perfusion pressure, with regadenoson (red curve), binodenoson (green curve), adenosine (blue curve), and CGS-21680, an unsuccessful dilator that has been withdrawn. (Adapted with permission of (31).) (D) Shown is increased coronary flow with adenosine (left) and binodenoson, WRC-470 (right) in a dog with tight stenosis of left anterior descending (LAD) coronary artery but without evident left circumflex (LCX) disease. Flow at baseline is shown in black, and flow with respective dilators is shown with hatched bar. Note blunted LAD response; LCX responds fully, given presence of flow-limiting agent. The binodenoson seems to bring same or higher flow response. (Adapted with permission of (34).)

View larger version (35K): [in this window] [in a new window]   FIGURE 6.  (A) Correlations with 4 dosing regimens. Summed defect scores (SDS) generated with adenosine correlated well with those using binodenoson in a 1.5 µg/kg bolus dosage. (B) Shown are rest and stress adenosine and binodenoson perfusion images in 2 case examples (patients A and B). Agreement is apparent. (Adapted with permission of (30).)

View larger version (43K): [in this window] [in a new window]   FIGURE 7.  (A) Shown are agreement rates between adenosine–adenosine images (orange bars) and regadenoson–adenosine images (blue bars) based on presence or absence of reversible defects. Equality between these comparisons is evident. (B) Shown are agreement rates between adenosine–adenosine images (orange bars) and regadenoson–adenosine images (blue bars) by SSS, the summed stress score, based on a 17-segment model. Again, equality is evident. (C) Shown are SPECT images obtained with adenosine (top), with regadenoson (middle), and at rest (bottom) in 3 orthogonal views. Lateral reversible defect is seen on both sets of images and is more prominent with regadenoson. Rev. Def. = reversible defect. (Adapted with permission of (35).)