CHAPTER 26 Pharmacologic Stress Agents

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As imaging modalities for the detection of heart disease continue to evolve and the elderly patient population expands, alternatives to traditional exercise stress testing are becoming more important in clinical practice. Increasingly, patients with conditions precluding exercise treadmill testing are being referred for diagnostic evaluations for possible coronary artery disease using pharmacologic stress tests. Exercise stress imaging provides significant diagnostic and prognostic information and is ideal for otherwise able patients. Not all patients can tolerate the rigorous activity inherent in an exercise treadmill test, however. In these patients, including patients with degenerative joint disease, pulmonary conditions, peripheral vascular disease, congestive heart failure, and other systemic processes that prevent the attainment of adequate exercise stress levels, pharmacologic agents have become pivotal.

Two major categories of pharmacologic agents are most frequently used: vasodilators and inotropes. Although both types of agents can be used in either stress perfusion imaging or stress echocardiography, vasodilators have found their niche in nuclear perfusion studies, and inotropes have become more common in stress echocardiography. More recently, vasodilators and inotropes have been used for stress MRI, and vasodilators have been used for stress CT perfusion. This chapter explores both types of pharmacologic stress agents from their physiologic basis to their diagnostic and prognostic value. The clinical implications of each modality and their inherent advantages and disadvantages are specifically emphasized.

VASODILATOR AGENTS

Vasodilators are primarily used in single photon emission computed tomography (SPECT) myocardial perfusion imaging with radiotracers such as thallium 201 and Tc 99m. As positron emission tomography (PET) and MRI perfusion studies become more ubiquitous, these agents are expected to have an expanding role. The two agents most extensively studied and in current clinical use are adenosine and dipyridamole. The use of these vasodilators was spurred by insight into the pathophysiology of coronary blood flow (CBF). Their utility continues to grow based on a wealth of clinical evidence and expanding indications and imaging modalities.

Coronary Blood Flow

As heart muscle contracts during systole, the myocardium impedes its own blood supply because most CBF occurs during diastole. This pulsatile flow is conducted through a highly curved, branching vascular system composed of larger epicardial vessels and smaller intramural vessels. While epicardial coronary arteries serve as conductance vessels, intramural arteries distribute and regulate blood flow. This adaptation, termed autoregulation, occurs rapidly in response to changes in myocardial oxygen demands, primarily through functional hyperemia.¹ This ability of the coronary tree to alter its resistance and increase CBF in response to myocardial metabolic demands is maintained by a balance between vasoconstrictors, such as endothelin, and vasodilators, such as nitric oxide. Acting in smaller arteries and arterioles, these vasoactive factors are integral in allowing rapid, sustained adaptation of CBF based on the requirements of the myocardium.

Coronary Flow Reserve

As atherosclerosis develops in epicardial coronary arteries, the resulting stenosis produces resistance to blood flow. The physiologic effect of a coronary stenosis depends on the degree to which the resistance to flow can be compensated by dilation of the microcirculation distal to the stenosis. This mechanism, regulated by vasoactive factors, maintains resting CBF at a constant level despite the presence of a growing burden of atherosclerosis. When an epicardial coronary constriction exceeds 80% to 90% of the normal segment diameter, the distal vasodilatory mechanisms are unable to compensate, and resting CBF cannot provide adequate oxygen to meet the resting needs of the myocardium.¹^,² When a stenotic vessel is exposed to a vasodilator (e.g., adenosine or dipyridamole) intended to induce hyperemic (or maximal) flow, the relative increase in flow decreases proportionately when a stenosis exceeds 50%, and is generally abolished at a 90% occlusion (Fig. 26-1).

FIGURE 26-1 Coronary flow reserve as a function of coronary artery diameter narrowing. Maximum (i.e., hyperemic) coronary blood flow and normal resting coronary artery flow are depicted. With progressive narrowing, resting flow is not affected until 80% to 90% stenosis, whereas hyperemic flow is impaired at 50% narrowing.

(From Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing critical coronary stenosis: instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974; 33:87-94.)

This concept of coronary flow reserve is integral to understanding the physiologic effects of chronic atherosclerosis within the lumen of the coronary tree. The response of coronary arteries to vasodilators depends on the degree of stenosis and the chronic effects of coronary flow reserve at the time of vasodilator administration.

Coronary Blood Flow and Radiotracer Uptake

Vasodilators can increase CBF five times normal levels. This large increase in CBF occurs in myocardium supplied by normal coronary arteries, in contrast to the lack of an increase to myocardium supplied by stenosed arteries as discussed previously; this forms the basis for vasodilator perfusion imaging (Fig. 26-2). If the myocardial uptake of radiotracers such as thallium 201 and Tc 99m were purely linear and based on CBF, a high level of image contrast would theoretically exist between myocardium supplied by normal arteries (i.e., without stenosis) and arteries with hemodynamically significant stenoses. In reality, the extraction fraction of most tracers decreases when CBF increases beyond 2.5 times baseline values. The practical effect of this “roll-off” in the uptake-flow relationship is a physiologic constraint in detecting mild-to-moderate stenoses. The flow increase in response to vasodilators in vessels with a mild-to-moderate stenosis may still be two to three times normal because of coronary flow reserve. This prevents differentiation with a normal coronary artery owing to radiotracer roll-off at a fixed level of hyperemic flow because the normal and mildly stenotic arteries would have identical tracer uptake. Generally with the more common radiotracers, it is difficult to identify noninvasively stenoses that are less than 50% because of the preservation of CBF in the resting and hyperemic states through natural vascular response mechanisms.

FIGURE 26-2 Comparison of coronary flow at rest versus hyperemia. A, Myocardial flow proximal and distal to a stenosis are equal at rest. B, Myocardial flow with hyperemia increases four times above resting flow in the arteries with no coronary artery disease. In the territory supplied by the stenotic artery, hyperemic flow increases only twofold. As a result, radiotracer uptake is relatively decreased in the territory supplied by the stenotic vessel, resulting in a perfusion defect.

(Adapted from Iskandrian AE, Verani MS. Nuclear Cardiac Imaging: Principles and Applications. New York, Oxford University Press, 2003.)

Adenosine

Adenosine is a small heterocyclic compound that is endogenously produced in variable amounts as part of a normal cellular metabolism and during ischemia. Through adenosine receptors, it serves as a potent coronary vasodilator (adenosine A₂ receptors) and inhibitor of the sinoatrial and atrioventricular (AV) nodes (adenosine A₁ receptors).³ Adenosine is produced intracellularly, but interacts on the adenosine receptors on the outer cell membrane (Fig. 26-3). Theophylline and caffeine act at these receptors as competitive blockers, reducing the effects of adenosine.

FIGURE 26-3 Schematic of the mechanism of action of dipyridamole and adenosine. Exogenously administered adenosine acts directly on its receptor to result in coronary arteriolar vasodilation, and an increase in myocardial blood flow (MBF) as resistance is minimized. The adenosine A_2a receptor mediates coronary arteriolar vasodilation, which is the basis for pharmacologic stress testing. Dipyridamole blocks the intracellular retransport of adenosine and inhibits adenosine deaminase (ADA), resulting in increased intracellular and interstitial concentrations of adenosine, which then interacts with its receptor.

(Adapted from Follansbee WP. Alternatives to leg exercise in the evaluation of patients with coronary artery disease: functional and pharmacological stress modalities. In Gerson MC [ed]. Cardiac Nuclear Medicine. New York, McGraw-Hill, 1997.)

Clinically, adenosine is infused intravenously and has a very short half-life of less than 2 seconds. As a result, the time-to-peak effect occurs in the first minute of infusion. Adenosine is given typically as a continuous infusion of 140 µg/kg/min for 4 to 6 minutes, with radiotracer injection halfway into the infusion. To avoid an unintended rapid bolus of residual adenosine, radionuclide dose injection and flushing and adenosine infusion should be done through separate intravenous lines or through the use of a dual port.³ Hemodynamically, adenosine causes a modest decrease in systolic blood pressure and increase in heart rate, in total leading to an increase in cardiac output and mild increase in pulmonary capillary wedge pressure.

Side effects are common with adenosine infusion, occurring in more than 75% of patients (Table 26-1). These side effects are transient, usually resolving within 1 to 2 minutes of stopping the infusion, and rarely require reversal with aminophylline. Most side effects are related to stimulation of the adenosine A₁ and A₃ receptors. Chest pain is common, although it is not specific for the presence of coronary artery disease, occurring in patients with no coronary artery disease at the same frequency as in patients with documented coronary artery disease. Although stimulation of the adenosine A₃ receptors can theoretically lead to bronchospasm, most dyspnea occurring with adenosine infusion is likely related to hyperventilation. Caution should be used in patients with a history of asthma, severe chronic obstructive pulmonary disease (COPD), or active wheezing because of the potential for bronchospasm. Changes in AV conduction usually result in transient first-degree or second-degree AV block. Most bradyarrhythmias are transient and resolve despite continued adenosine infusion.

TABLE 26-1 Side Effects of Pharmacologic Stress Agents

Dipyridamole

Dipyridamole is a pyrimidine base that induces vasodilation by elevating blood and interstitial levels of adenosine. By blocking reuptake of adenosine into cells, dipyridamole increases extracellular levels of adenosine, allowing interaction with adenosine A₂ receptors on the outer cell membrane. Activation of the adenosine A₂ receptor leads to a complex series of events mediated by G proteins and leading to a decrease in intracellular calcium uptake, culminating in coronary vasodilation (see Fig. 26-3). Dipyridamole also exhibits antiplatelet activity, likely related to phosphodiesterase inhibition, increased adenosine triphosphate (ATP) levels, potentiation of aspirin effects, and increased adenosine.³

Clinically, dipyridamole is infused intravenously and has a biologic half-life of 88 to 136 minutes. It is given as a continuous infusion of 0.57 mg/kg over 4 minutes, with radiotracer injection 3 to 4 minutes after the dipyridamole infusion is completed. This is distinct from adenosine, where tracer injection is during vasodilator infusion (Fig. 26-4). The standard intravenous dose of dipyridamole results in a slight increase in heart rate, a decrease in systolic blood pressure, a modest increase in cardiac output, and a slight increase in pulmonary capillary wedge pressure.

FIGURE 26-4 Pharmacologic stress protocols based on nuclear perfusion imaging. Dobutamine is incrementally increased to a maximum dose of 40 µg/kg/min. If target heart rate has not been reached, the addition of 0.5 to 1 mg of atropine is typically needed. Echocardiographic images are typically obtained at the beginning of the dobutamine infusion, and at prespecified intervals to include peak heart rate and recovery phases. Tracer can be injected for perfusion imaging after target heart rate is reached.

(Adapted from Zaret BL, Beller GA. Clinical Nuclear Cardiology: State of the Art and Future Directions, 3rd ed. Philadelphia, Mosby, 2005.)

Side effects occur in about 50% of patients and include chest pain, nausea, dizziness, and headache (see Table 26-1). As with adenosine, chest pain is mostly nonanginal and does not correlate with the presence of coronary artery disease. Bronchospasm is rare, but can be precipitated in patients with asthma or severe COPD. Arrhythmias, including AV block, are highly uncommon. Dipyridamole has generally been extensively studied and has an excellent safety record. Most significant side effects can be reversed with slow intravenous administration of theophylline (100 to 300 mg), which is a competitive blocker of adenosine receptors.