An exercise stress test is recommended as the method of choice when performing myocardial perfusion SPECT, and the perfusion tracer is injected during maximum cardiac exertion. To avoid injecting the perfusion tracer at submaximum exertion and thereby risking a false-negative test, injection should be done when the heart rate is above 85% of the age-predicted maximum. This can be calculated by the following formula: (220 – age) × 0.85. After injection, the patient should continue exercise for 1 minute to make certain that the perfusion tracer has entered the cells and left the blood pool. The workload can be lowered somewhat to enable the patient to continue exercise for 1 whole minute. Contraindications for an exercise stress test and criteria for termination of the test before reaching the age-predicted heart rate are the same as for a standard exercise stress test according to the international recommendations.16 Contraindications include any acute or ongoing severe cardiopulmonary disease, such as acute coronary syndrome, aortic dissection, cardiac failure or complex arrhythmias with hemodynamic instability, pulmonary embolism, severe hypertension (blood pressure >200/110 mm Hg), and severe aortic stenosis. Absolute indications for early termination of the exercise test include significant decrease in blood pressure, severe angina, sustained ventricular tachycardia, pathologic ST-segment elevation (>1 mm in leads with no Q waves other than V1 or aVR), increasing nervous system symptoms, or signs of poor perfusion. If there are technical difficulties affecting the ability to record ECG and blood pressure, the test should be terminated, and the problems should be fixed before continuing. Relative contraindications include marked ST-segment depression (>3 mm), arrhythmias such as triplets of premature ventricular contractions or supraventricular tachycardia, development of left bundle branch block, and severe hypertension (>250/130 mm Hg).
Pharmacologic Stress Test
Pharmacologic stress with adenosine, dipyridamole, regadenoson, or dobutamine can be used to cause coronary vasodilatation in patients who cannot perform a maximum exercise stress test, including patients with orthopedic problems and patients who cannot reach adequate heart rate because of β-blockers or a concomitant disease such as chronic obstructive pulmonary disease or kidney failure. A vasodilator drug is also used in patients with left bundle branch block or a pacemaker with ventricular stimulation because of potential false-positive perfusion images when using the exercise stress test (see "Pitfalls" later). Pharmacologic stress is used most commonly with PET imaging. Direct vasodilatation is caused by adenosine, dipyridamole, and regadenoson. Dobutamine is a sympathomimetic drug with positive inotropic and chronotropic properties that causes a secondary vasodilatation. Pharmacologic stress testing is safe under correct monitoring and patient supervision. ECG, blood pressure, and patient status should be assessed and supervised by a physician, and cessation of the drug and use of antidotes may be necessary.
Adenosine is the most commonly used pharmacologic stress agent and acts as a direct vasodilator on the coronary vessels by binding to the A2A receptor on the arterioles. Adenosine is given as a continuous infusion in a peripheral vein for 5 to 6 minutes. The half-life of adenosine is very short (<10 seconds), and therefore, no antidote is needed. After cessation of the infusion, the effect stops. Adenosine is given at a dose of 140 μg/kg/min, but the dose can be lowered if adverse effects occur. Common adverse effects to adenosine are flushing, headache, chest discomfort, and dyspnea. These adverse effects are unspecific and not related to ischemia; therefore, patients are informed of their benign nature, and most patients can tolerate them. Criteria for early termination of adenosine infusion are persistent high-grade atrioventricular (AV) block or sinoatrial block, severe hypotension, bronchoconstriction, and severe angina. Adenosine causes AV block in high doses, and especially in older patients, transient AV block is seen. Lowering the adenosine dose is often sufficient to avoid high-grade AV block. Blood pressure drops in many patients because of the vasodilatation, but there is rarely a need to stop the infusion. A profound decrease of blood pressure is related to a worse patient status and ischemia, and in some patients, adenosine infusion has to be terminated. Healthy subjects given adenosine do not experience a drop in blood pressure but do experience an increase in the heart rate and stroke volume to maintain the blood pressure. Bronchoconstriction is a rare but potentially severe adverse effect of adenosine and is the reason for the contraindication of adenosine in patients with active asthma or severe chronic obstructive pulmonary disease. In patients with mild chronic obstructive pulmonary disease, premedication with inhalation of β2 stimulants can be used. Auscultation of the lungs during adenosine infusion can be used to detect bronchoconstriction. Of note is that the dyspnea experienced by most patients is not related to bronchoconstriction. Dyspnea is believed to be caused by stimulation of the peripheral oxygen receptors in the carotid sinus. The safety of adenosine has been assessed in a large study of over 9000 patients; 0.1% of patients experienced bronchoconstrictions, although patients with asthma and severe chronic obstructive pulmonary disease were excluded from receiving adenosine. Two patients experienced severe complications with pulmonary edema and myocardial infarction, respectively. The combination of the adenosine infusion with physical exercise on a bicycle ergometer or treadmill decreases adverse effects. The increase in sympathetic activity during exercise increases blood pressure and decreases the risk of AV block and possibly bronchoconstriction. Furthermore, the blood supply to the gastrointestinal tract decreases and hence tracer uptake in that region, which is advantageous for the subsequent SPECT acquisition. In patients with left bundle branch block and pacemakers with ventricular stimulation, adenosine infusion should not be combined with physical exercise (see later section "Pitfalls").
Dipyridamole acts via the endogenous adenosine of the body by inhibiting the reuptake of adenosine and thereby raising the concentration around the receptor. Because of its long half-life, an antidote is needed, and theophylline is most commonly used. Adverse effects to dipyridamole are similar to those of adenosine.
Regadenoson is a specific A2A receptor agonist recently made available with similar diagnostic results as adenosine.17 The effect of regadenoson is sustained, with a half-life of 2 to 3 minutes. Therefore, an antidote such as theophylline is often used. Because of its specific A2A receptor characteristics, regadenoson can be used in chronic obstructive pulmonary disease and asthma patients. Regadenoson was approved in the United States in 2008.
Dobutamine is a sympathomimetic drug with positive inotropic and chronotropic properties that causes secondary vasodilatation. The infusion rate is increased in steps, starting at 5 or 10 μg/kg/min and increasing every third minute to 20, 30, and 40 μg/kg/min. Blood pressure and ECG are monitored continuously, and criteria for termination of infusion and contraindications are the same as for an exercise stress test. Injection of the radioactive tracer is performed at 85% of the age-predicted heart rate, which often occurs only after adding atropine starting at a dose of 0.25 mg. It is important that β-blockers are discontinued before the test in order to reach the age-predicted heart rate. Common adverse effects of dobutamine are headache, nausea, anxiety, and atypical chest pain. Angina and ventricular arrhythmias need to be monitored, and paroxysmal atrial fibrillation can be triggered by dobutamine. If the termination criteria are followed, severe complications such as myocardial infarction and death are extremely rare. When discontinuing the infusion, the effect of dobutamine lasts longer compared with adenosine, and sometimes an intravenous injection of a β2-blocker is needed. There are additional contraindications for the use of atropine (eg, narrow-angle glaucoma).
Medication and Caffeine before Myocardial Perfusion Imaging
Oral nitrates should be avoided before stress because of their anti-ischemic effect. If an exercise test or dobutamine infusion is used, β-blockers and heart rate–lowering calcium blockers should be discontinued 48 hours before the injection. A common indication for vasodilator perfusion imaging is inappropriate heart rate response in patients who cannot or who have forgotten to discontinue their medication. The amount of ischemia will be less if anti-ischemic medication is maintained even with vasodilator stress tests,4 however, with β-blockers, not to the extent that it affects the sensitivity and specificity.18 Caffeine needs to be discontinued before adenosine, dipyridamole, and regadenoson because of a competitive blockage of the adenosine receptor. Abstinence from caffeine is recommended for preferably 24 hours.