Introduction

Cardiac stress testing is the most commonly used modality for diagnostic purposes in patients with known or suspected coronary artery disease (CAD). The utility of stress testing should be interpreted based on the likelihood of the disease. Patients with a low probability of disease have a high risk of false-positive results and may end up further unnecessary invasive testing without changing patient outcomes. Those with high pretest probability have a high risk of false-negative results that can miss a critical diagnosis; therefore, these patients should proceed directly to more confirmatory testing such as cardiac catheterization.

Stress testing is most clinically useful in intermediate-risk patients for CAD that will help further reclassify these patients into low risk and high-risk depending on the stress test result. Stress testing can also be used to obtain prognostic information to determine the patient's response to optical medical therapy, measure exercise capacity, evaluate ischemia who are already started on medical therapy for known CAD. In general exercise, stress is preferred because it provides a gauge of functional capacity, exercise tolerance, and symptom provocation.[1] Pharmacologic stress testing is an alternative modality in patients who are unable to exercise and with the following conditions:

1. Patients presenting with unstable angina.
2. History of heart failure which is not well controlled, and there is a concern for deterioration.
3. Poorly controlled blood pressure with systolic blood pressure significantly higher (>200 mmHg at rest).
4. Patients with a history of aortic stenosis which is significantly worse on echocardiogram (aortic valve area <1.0 cm2 and mean gradient >40 mmHg) and have ongoing symptoms.[2]
5. Myocardial infarction in the last week.
6. Acute pulmonary embolism
7. Acute inflammation of pericardium or myocardium
8. Severe pulmonary hypertension

Exercise stress testing is also not very helpful in patients with an insufficient hemodynamic response to exercise due to abnormalities involving the respiratory system, and having ongoing issues involving muscles, bones, and vessels in the peripheral system. Also, the exercise stress test is not useful when baseline EKG is abnormal such as with left ventricular hypertrophy (LVH), left bundle branch block (LBBB), paced rhythm, Wolff Parkinson White (WPW) syndrome, or greater than 1 mm ST-segment depression. These patients are suitable candidates for testing involving pharmacologic agents. Pharmacologic stress testing is used in combination with imaging modalities such as radionuclide imaging and echocardiography.

Specimen Collection

Pharmacological stress testing is a highly supervised procedure conducted under expert medical personnel supervision either in clinic or hospital. During the procedure, the patient will have electrodes attached to their chest, and also their vital signs are continuously monitored. The stress agent is injected through a peripheral intravenous line, which will increase blood flow through the coronary vasculature and mimic a response similar to exercise stress testing. Once a peak effect is attained, a small amount of radioactive material is inserted through the peripheral intravenous line. After that, a high-resolution gamma camera takes several pictures of the heart to get a better visualization of your coronary vasculature. During the resting phase, the gamma camera will take additional pictures which can be used as a comparison to the stress-induced perfusion imaging.

Procedures

Vasodilator agents currently approved by the Food and Drug Administration (FDA) include:[1][3]

1. Adenosine
2. Dipyridamole
3. Regadenoson

Vasodilators do not really stress the heart and create a coronary steal phenomenon by temporarily increasing blood flow to non-diseased vessels of the coronary vasculature at the expense of diseased vessels that can be visualized on nuclear imaging.

Regadenoson is a newer vasodilator agent approved by the FDA in 2008 and most routinely used today due to its selective action on A2A receptors and lesser side-effects.

Dobutamine is an alternative drug that acts as an inotrope and can be used in pharmacological stress testing. It is not approved by the FDA and rarely used currently. However, it can be used in patients who have contraindications to pharmacologic vasodilator stress agents such as in patients who have severe respiratory diseases like asthma or chronic obstructive pulmonary disease (COPD) or when regadenoson is not readily available for these patients.

Indications

1. Patients who are unable to tolerate exercise stress test due to abnormalities involving the respiratory system (severe chronic obstructive pulmonary disease (COPD)), provoked angina, hypotension during exercise, chronotropic incompetence. These patients are suitable candidates for testing involving pharmacologic agents.[4]
2. Patients who have baseline abnormal electrocardiogram which include the presence of left bundle branch block at baseline, left ventricular hypertrophy, paced rhythm, Wolf Parkinson White syndrome, and greater than 1 mm ST-segment depression. These patients can have false-positive results on an exercise stress test.
3. Symptomatic aortic stenosis.[4]

Potential Diagnosis

Medications used for stress testing diagnosis include all of the following.

Adenosine

Adenosine acts on the coronary arteries through specific activation of the A2A receptor and causes them to dilate.[5][6] There are 4 types of adenosine receptors: A1, A2A, A2B, and A3.

• Activation of the A1 receptor results in decreased atrioventricular conduction and reduces heart rate.
• Activation of A2A receptors in vascular smooth muscles in blood vessels such as in coronary arteries causing vasodilation
• Activation of the A2B and A3 receptors in bronchial beds can also result in bronchospasm.

Dose:

The dose of adenosine used during a pharmacologic stress testing is 140 mcg/kg/min, and it is given continuously for 6 minutes duration. The radioactive material is normally given at 3 minutes, and then adenosine is kept infusing for 3 more minutes. There is an additional methodology in which adenosine is given for 4 minutes as a continuous infusion, and its effects and outcomes are comparable to the continuous infusion lasting for 6 minutes.[7] Adenosine generally produces a modest increase in heart rate and a modest decrease in blood pressure. The infusion results in a 3.5- to 4-fold increase in coronary blood flow over baseline. The half-life of adenosine is less than 10 seconds.[1]

Limiting caffeine intake:

Methylxanthines such as theophylline or caffeine, block adenosine binding due to antagonistic action at A2A receptors and can reduce the coronary vasodilation effects of adenosine. Therefore, it is recommended to discontinue consumption of caffeine-containing medications, foods, or beverages for at least 12 hours and ideally 24 hours before adenosine stress testing.[8]

Contraindications:

1. Adenosine is contraindicated in patients with reactive airway disease with significant wheezing
2. Patients with a history of advanced conduction abnormalities, including 2nd or 3rd-degree atrioventricular block in the absence of a permanent pacemaker.
3. Patients with a history of abnormalities in the sinus node in the absence of a permanent pacemaker
4. Systolic blood pressure of less than 90 mmHg
5. Poorly controlled blood pressure with systolic blood pressure significantly higher (over 200 mmHg at rest).
6. Caffeine intake in the previous 12 hours
7. Known hypersensitivity to adenosine
8. Patients with acute coronary syndrome or unstable angina or who experienced a myocardial infarction less than 1 week ago.

Dipyridamole

Dipyridamole was the first vasodilator used for myocardial perfusion stress testing. It is an indirect coronary artery vasodilator. It increases the tissue levels of adenosine by preventing the intracellular reuptake of adenosine by inhibiting enzyme adenosine deaminase prolonging its vasodilator effect and increasing adenosine blood levels.[9][10]

Dipyridamole increases coronary blood flow to 3.8 to 7 times than baseline. The alpha half-life (the initial decline following peak concentration) is approximately 30 to 45 minutes. The beta-half life (the terminal decline in plasma concentration) is approximately 10 hours. It is metabolized in the liver to glucuronic acid conjugate and excreted in the bile.

Dipyridamole dose:

The dose of dipyridamole is 0.142 mcg/kg/min, or 0.57 mcg/kg.[9] Dipyridamole is infused over 4 min, with the radiotracer being injected 3 to 5 min after the completion of the dipyridamole infusion. Symptoms may last for a longer time than other vasodilators (15 to 25 minutes). 

Side effects of dipyridamole:

1. The incidence of atrioventricular (AV) block with dipyridamole is less than that observed with adenosine (2%).
2. Chest pain is seen in 20% but is nonspecific and not necessarily indicative of the presence of CAD.
3. Minor side effects include headache, dizziness, nausea, hypotension, and flushing.

Contraindications:

1. Patients with bronchospastic lung disease with ongoing wheezing or history of significant reactive airway disease should not undergo dipyridamole stress testing.
2. Uncontrolled hypertension (systolic pressure of over 200 mmHg or a diastolic pressure of over 110 mmHg)
3. A systolic blood pressure of less than 90 mmHg.
4. Known hypersensitivity to dipyridamole.
5. Caffeine intake in the previous 12 hours
6. Second- or third-degree atrioventricular block without a functioning pacemaker.

Regadenoson

Regadenoson is another direct coronary artery vasodilator, which is a selective A2A agonist. The affinity with which regadenoson binds with A2A is 10 times greater than its affinity to bind with the A1 receptor and even weaker affinity to bind with A2B and A3 receptors. Regadenoson produces maximal hyperemia quickly and maintains it for an optimal duration that is more practical for radionuclide myocardial perfusion imaging. Regadenoson's simple, rapid bolus administration in all patients, regardless of weight and short duration of hyperemic effect, has greatly simplified the method of stress testing as compared to adenosine and dipyridamole. It is the most commonly used currently due to lesser side effects and easier to perform.[11]

Regadenoson dose:

As mentioned earlier, the dosing of regadenoson is not weight-based like other vasodilators. The dose of regadenoson normally used is 0.4 mg, which is available only in a prefilled 5-ml syringe. The dose is immediately followed by a saline flush. The radiotracer is administered 10 to 20 seconds later, immediately followed by another saline flush.[12] The results of the ADVANCE MPI 2 trial have shown that regadenoson is non-inferior to adenosine for the detection of reversible defects and is safe and better tolerated.[13] The half-life of regadenoson is 2 hours.

Contraindications:

1. Regadenoson is considered contraindicated for patients with second- or third-degree AV block or sick sinus syndrome.
2. Allergic response in the past to the agent
3. Hypotension with systolic blood pressure <90 mmHg.
4. Poorly controlled blood pressure with systolic blood pressure significantly higher (greater than 200 mmHg at rest)
5. Patients who received dipyridamole in the last 2 days should also avoid regadenoson stress testing.
6. Patients with acute coronary syndrome or unstable angina or who experienced a myocardial infarction less than 1 week ago
7. Caution is advised in patients with reactive airway disease with wheezing

Reversal of vasodilator effects:

In patients who suffer from undesirable effects from pharmacologic stress testing agents, caffeine is given generally to counteract the effects. The use of caffeine in reversing the side effects is more beneficial in dipyridamole and regadenoson due to longer duration of action as compared to adenosine. Aminophylline can be used for more threatening side effects.

Dobutamine

Dobutamine is an inotropic agent that can be used for myocardial perfusion stress testing.[1] Dobutamine is not approved by the Food and Drug Administration for pharmacologic stress testing and rarely used currently. Dobutamine is a beta-agonist that results in the stimulation of beta1 and beta2 receptors.[14]

Dobutamine, like exercise, increases myocardial oxygen demand and evokes ischemia if there is insufficient perfusion to the affected myocardium that can be seen on stress echocardiography or nuclear imaging.

Beta-blockers should be held 24 hours before the dobutamine stress test due to the opposite antagonistic action.

Dobutamine dose:

Dobutamine is given as an infusion as an incremental dose beginning at 5 or 10 mcg/kg/min for 3 minutes. It is increased to 20, 30, and then 40 mcg/kg/min, also for 3-min intervals, for a maximum of 12 minutes or until the target heart rate is achieved. Radiotracer is injected at peak heart rate with dobutamine infusion continuing for one minute following tracer injection. The half-life of dobutamine is 2 to 3 min. 

Indications:

1. Dobutamine is a secondary pharmacologic stress agent that is recommended only in patients who cannot undergo an exercise stress test and also have contraindications to pharmacologic vasodilator stress agents such as high degree AV block or reactive airway disease (if regadenoson is not available).

Contraindications:

1. Patients with acute coronary syndrome or unstable angina or who experienced a myocardial infarction less than 1 week ago
2. Hemodynamically significant left ventricular outflow obstruction.
3. Atrial tachyarrhythmias with an uncontrolled ventricular response
4. Hypertension (systolic blood pressure over 200 mmHg or diastolic blood pressure exceeding 110 mmHg)
5. Aortic dissection
6. Known hypersensitivity to dobutamine

Normal and Critical Findings

Pharmacological stress testing with myocardial perfusion imaging can help to detect perfusion or wall motion abnormalities that indicate either infarction (seen on stress and rest images) or ischemia (seen on stress images only). The utility of cardiac stress testing is determined in part by pretest disease probability; false-positive results may lead to potential downstream testing and treatment. Conversely, in patients with high CAD pretest probability, false-negative studies lead to a missed diagnosis. Therefore, the greatest use is in patients with intermediate CAD probability, in whom a positive test significantly increases disease likelihood, and negative test significantly decreases the likelihood. Depending on that, further testing, such as coronary angiography, can be considered. 

Interfering Factors

1. Caffeine and methylxanthines intake within 12 hours prior to stress testing with vasodilator stress agents.

2. Beta-blockers taken in the last 24 hours if the patient is going for dobutamine stress testing.

Complications

Pharmacological stress testing is a relatively safe procedure with minimal side effects, but patients can occasionally suffer from undesirable side effects based on the mechanism of action of the pharmacologic stress agent used. Vasodilator agents, including adenosine, dipyridamole can produce bronchospasm and AV block. Less common with regadenoson due to its selective action. Dobutamine can cause tachyarrhythmias.

Patient Safety and Education

Caffeine is commonly offered to patients after the stress testing procedure, as it will likely reverse undesirable side effects. It is particularly helpful with regadenoson and dipyridamole, as they have a longer half-life than adenosine. More serious side effects can be treated with aminophylline, which is an adenosine receptor antagonist.[1] Beta-blockers can be used to treat side effects or toxicity caused by dobutamine.

Clinical Significance

In the majority of patients with an inability to exercise, pharmacologic stress testing is an essential diagnostic modality and widely used for the evaluation of ischemia and coronary artery disease (CAD). It is also used to assess prognosis in individuals with known CAD.[15]