Pharmacologic Stress Cardiac Imaging

Pharmacologic Stress Cardiac Imaging

Pharmacologic stress can be performed in patients that are unable to perform adequate exercise as a result of orthopedic or cardiopulmonary limitations [48]. Pharmacologic stress can be performed using either vasodilator agents (such as dipyridamole or adenosine) or dobutamine. Patients with normal pharmacologic vasodilator stress SPECT exams have a generally good prognosis (annual risk of cardiac death or infarction of 1.3%-2.3%)- although this is slightly worse than the event rate in patient with normal exercise stress exams (which is less than 1%) [28,35,38,42]. This is likely related to a greater degree of co-morbid conditions in patients that are selected for pharmacologic stress [38]. Typically, patients selected for pharmacologic stress are older and have a higher prevalence of hypertension, diabetes, previous MI, and revascularization procedures [38]. Patients with reversible defects on pharmacologic stress exams also have a higher cardiac event rate than similar patients with exercise stress (about 11% versus 5.6%) [38].

The presence of ischemic changes on ECG during pharmacologic stress is uncommon (between 1% to 7% of patients) [28,29] and is generally found in combination with reversible perfusion defects on perfusion imaging [42]. During vasodilator stess, the phenomenon is felt to be the result of a "coronary steal" and may be associated with the presence of multivessel coronary artery disease [42]. It is postulated that the pharmacologic vasodilatation produces less vasodilatation in vessels that have fixed stenoses [42,51]. Meanwhile, the resistance in normal coronary vessels will drop and this can cause blood flow to be diverted away from collateral vessels supplying vascular beds distal to diseased vessels with a critical stenosis [42,51]. This decrease in perfusion in the diseased vessel (which is collateral dependent) then leads to the development of ischemia [42]. Ischemic ECG changes noted during pharmacologic stress is a marker for increased cardiac event rates [42]. Patients that develop ECG evidence for ischemia with vasodilator stress should be further evaluated even if the SPECT images are normal [29]. In patients with normal pharmacologic stress images, the presence of ischemic ECG changes is associated with a higher risk for subsequent cardiac events (4%-7.5% at one year) [28,29]. Similar to vasodilator stress, the presence of ischemic ECG changes during dobutamine infusion also carries a higher risk for subsequent cardiac events (about 4% annual risk) [42].

Advantages

• Provides a standardized, consistent stress independent of patient endurance. A pharmacologic stress exam is likely to be more sensitive than a submaximal exercise scan for the detection of CAD.
• Not affected by antianginal drugs
• Greater increase in coronary flow than exercise stress (up to 4ml/min./gm which is 4 to 6 times baseline)

Drawbacks:

• Myocardial extraction of Tc-99 perfusion agents (tetrofosmin, sestamibi, and to a lesser extent thallium) is not linear during adenosine or dipyridamole induced hyperemia [19]. At higher flow rates (greater than 2 times baseline [2.5 to 3.0 mL-min^-1 - gm^-1]), there is decreased tracer extraction [19,47]. This decreased extraction results in underestimation of flow heterogeneity and can potentially result in underestimation of  myocardial ischemia [19].

Indications for pharmacologic stress:

• Patients who cannot exercise adequately for diagnostic purposes such as patients with peripheral vascular disease in whom claudication is the rate limiting factor for exercise. Perfusion defects can be missed or underestimated in patients with submaximal exercise stress.
• Left bundle branch block: Pharmacologic stress should not result in a reversible septal defect as the heart rate should not increase significantly.
• Fixed rate ventricular pacemakers: In paced patients, the ECG is not interpretable on standard tredmill testing [40]. Pharmacologic stress provides significant prognostic information in patients with permanent pacemakers and can identify patients at high risk for subsequent cardiac events [40].
• Pre-operative risk stratification
• Risk stratification in the early post myocardial infarction period: During the early post-MI period, evidence of a reversible perfusion abnormality on the dipyridamole exam was the best predictor of future cardiac events in one study. [1]

Dipyridamole

Physiology & Pharmacology

Dipyridamole stress tests coronary flow reserve without increasing myocardial oxygen demands. Following injection, a radiotracer will preferentially go to areas perfused by normal coronary arteries, and proportionately less to areas supplied by stenotic vessels. 

Dipyridamole acts indirectly via adenosine. Adenosine is normally produced by both the myocardial smooth muscle and endothelium [42]. Dipyridamole inhibits adenosine uptake by the vascular endothelium and alters red cell membranes thus preventing access to membrane bound adenosine deaminase which is the enzyme primarily responsible for adenosine degradation. This results in reduced degradation and increased blood levels of adenosine (it approximately doubles the circulating levels of adenosine). Adenosine then binds to A_2a receptors which predominate in the cell walls of the coronary arteries which results in vasodilatation [42]. Adenosine is a potent arteriolar dilator and the resultant dilatation in the precapillary and arteriolar capillary beds results in 3 to 5 fold regional coronary flow augmentation in normal vessels [30] (this frequently exceeds the augmentation in coronary flow by maximal exercise). Stenotic vessels with a limited coronary flow reserve demonstrate reduced responsiveness with relative flow reduction proportional to the degree of stenosis and a resultant defect on perfusion scintigraphy.

Dipyridamole is eliminated with a biological half-life of 90 to 135 minutes, while the peak vasodilatory effects occur approximately 2 minutes following completion of a 4 minute infusion and the effect persists for 10-20 minutes following the infusion [30]. Adenosine levels remain elevated for 30 to 45 minutes despite a relatively rapid fall in dipyridamole plasma levels [8]. Note that the coronary hyperemia induced with dipyridamole is less predictable than that seen with an adenosine infusion. Dipyridamole is metabolized primarily in the liver with only minimal amounts excreted in the urine [8]. Prolonged pharmacologic activity could occur in the setting of hepatic insufficiency [8].

Technique

Prep: Caffeine, theophylline, and aminophylline are non-selective inhibitors of adenosine. All theophylline (xanthine) and caffeine containing medications should be held for 36 to 48 hours prior to the exam. Caffeine containing beverages should be avoided for 24 hours [25]. Caffeine can reduce the hyperemic effect of dipyridamole by as much as 70% [12]. The percent heart rate increase has been found to be inversely correlated with the plasma caffeine level [25]. Patients with a caffeine level of zero have a mean increase in heart rate of 18% [25]. A less than 5% increase in heart rate may indicate a blunted response to the dipyridamole infusion [25]. It is not necessary to discontinue dipyridamole prior to the examination, however, other authors recommend that this medication be stopped for 48 hours [48]. The patient should be NPO for 4 to 6 hours prior to the exam to decrease splanchnic activity and reduce the possibility of nausea and emesis. Antianginal medication may alter both resting and dipyridamole induced hyperemic myocardial perfusion [32]. Nitroglycerine results in a slight (10%) increase in perfusion to areas supplied by stenosed and non-stenosed arteries [32]. Metoprolol in standard doses also reduces both resting and hyperemic perfusion, but the effect is more pronounced following dipyridamole infusion (about 25% decrease in hyperemic perfusion) [32]. The potential clinical consequence is reduced diagnostic sensitivity [32]. Unless specified by the referring physician, beta-blockers and nitrates should be withheld for 24 hours prior to the exam [48]. Amlodipine does not seem to affect perfusion [32].

Under the typical protocol, dipyridamole is infused at a rate of 0.142 mg/kg/minute for 4 minutes through a large vein. (Approximately 0.56 mg/kg) Oral administration is not routinely used because it results in erratic absorption and GI upset. During the infusion BP & HR are monitored each minute, and the EKG continuously. Patients may typically have a mild elevation in heart rate (5 to 10 bpm) and a modest decrease in blood pressure (10-15 mmHg). The peak pharmacologic effects occur about 6 to 8 minutes following initiation of the infusion. Effects persist for 15 to 30 minutes, but may last as long as 60 minutes.

A myocardial perfusion agent is injected 2 to 4 minutes following completion of the infusion (typically at 7 minutes) or sooner if impressive hemodynamic side effects are noted. Aminophylline (an adenosine receptor antagonist) may be administered I.V. 3 to 4 minutes after thallium to abort the dipyridamole effects after radionuclide extraction. Vasodilator infusions yield higher cardiac uptake of thallium than exercise stress, but unfortunately, produce worse heart-to-background ratios due to higher blood thallium levels and vasodilatation of the splanchnic bed which can result in high infradiaphragmatic background activity. Walking, bicycle ergometry, or low level exercise beginning near the completion of the dipyridamole infusion and continued for 30 to 60 seconds following injection of the radiotracer, will help to reduce the amount of gut and liver activity, produce heart-to-background ratios similar to exercise alone, and help to decrease the incidence of non-cardiac side effects (such as vasodilator induced hypotension) [3,4,14,15,48]. Low level exercise can also improve ECG sensitivity for the detection of ischemia [15]. Hand grip exercise has been used, but it may not be very effective [5]. The measured thallium washout rate is slightly slower than that following exercise.

A drawback of dipyridamole imaging is that the standard dose utilized may not produce maximal coronary vasodilatation in up to 20% of normal subjects (near maximal coronary vasodilatation occurs more consistently with adenosine). Preliminary work indicates that higher doses of dipyridamole (0.84 mg/kg infused over 6 minutes) are safe and may increase the sensitivity of the thallium exam (although not statistically significant in this particular study and certainly controversial as the larger dose was not felt to enhance the coronary vasodilatory effect of the standard dose in another study [6]). Side effects, however, are more common with the higher dose (up to 79% of patients). The most frequently encountered side effect was chest pain (58%). [7]

Contraindications

Contraindications to the dipyridamole exam include:

• Allergy to dipyridamole
• Acute myocardial infarction within the preceding 48 hours
• Unstable angina
• History of severe bronchospasm
• Hypotension (Systolic BP < 90 mmHg)
• Xanthines (caffeine or theophylline) within the preceding 24 hours. Dipyridamole induced hyperemia is attenuated by caffeine [34,36]. A serum caffeine level of 2 mg/L or higher has been predicted to increase the likelihood for a false-negative exam [25]. The plasma caffeine half-life for healthy subjects is between 4.9 to 5.7 hours and most patients will have a caffeine level of less than 1 mg/L after a 24 hour abstinence [34]. However, the half-life of caffeine is prolonged in patients with underlying liver disease and in patients taking oral contraceptives, cimetidine, or rifampin [36]. Medications containing dipyridamole or verapamil should be discontinued 48 hours prior to the test [48].

Side effects

Common, benign effects:

Side effects are common (50-60% of patients), but generally benign and typically relate to the agents peripheral vasodilatory effect. Chest pain (20-30%), flushing (15-30%), lightheadedness (20%), headache (15%), nausea (10%), extrasystoles (5%), mild hypotension (5%), and vomitting (rare). ECG abnormalities characterized by ischemic ST-segment depression (5%) is quite specific for the presence of CAD [8]. Chest pain is commonly atypical and is not an indicator of coronary artery disease as it is observed in normal subjects as well. The incidence of AV block is much less than that seen with adenosine.

Potentially more serious side effects include: (All are UNCOMMON)

1- Bronchospasm (0.2%)

Patients with a history of reactive airway disease or severe COPD may be at an increased risk for adenosine induced bronchospasm.

 2- Severe cardiac ischemia and myocardial infarction (0.1%)

Dipyridamole does not increase myocardial oxygen demands as does dobutamine. Ischemia is likely due to a combination of factors including loss of coronary autoregulation, reduced coronary perfusion pressure in the presence of full coronary dilatation, and the "Coronary Steal" phenomenon (blood is preferentially shunted to non-stenotic vessels with a reversal of flow from the abnormal to normal vascular beds through collateral vessels).

3- Severe hypotension (BP systolic<100 mm Hg)

4- Ventricular dysrhythmia

Rare- when seen, it should raise the suspicion of underlying CAD [2].

5- Stroke

Most likely related to an intracerebral steal phenomenon in a patient with unilateral high grade ICA stenosis or generalized decrease in cerebral blood flow with a watershed phenomenon [9,10].

Treatment of side effects

The antidote for dipyridamole is Aminophylline which rapidly (within minutes) reverses its effects. Aminophylline is given by a slow I.V. infusion 1-2 mg/kg slowly (Typically 75-100mg is adequate, up to 250mg if necessary). Aminophylline competitively blocks endothelial adenosine receptors [8]. It DOES NOT reduce circulating adenosine levels which remain elevated as long as dipyridamole is present. (NOTE: The half-life of dipyridamole is longer than that of aminophylline and side effects may recur after aminophylline has been metabolized). Concominant administration of nitroglycerin is often helpful in reducing ischemia

Sensitivity/Specificity for the Dipyridamole Exam (SPECT pharmacologic imaging)

Sensitivity and specificity for dipyridamole stress myocardial perfusion are virtually identical to exercise testing: Sensitivity: 85-90%; Specificity: 80-90%. As with exercise testing, increased lung uptake of the tracer on dipyridamole imaging also correlates with the presence of coronary artery disease [8]. 

Other authors have found that thallium scintigraphy with pharmacologic stress had a lower diagnostic accuracy (80%) in characterizing the extent and distribution of CAD in patients without prior myocardial infarction [11].

Note that patients with type II diabetes may have a significantly decreased hyperemic flow response (and lower flow reserve) to dipyridamole that is likely multifactoral and related to microvascular disease, endothelial dysfunction, and abnormalities in regional sympathetic innervation [47].

Adenosine

Physiology & Pharmacology

Similar to dipyridamole, adenosine imaging reveals coronary flow reserve- there is a decreased hyperemic response in myocardial regions supplied by stenotic vessels. Flow reserve (an indicator of adequate collateral circulation) is a better predictor of subsequent cardiac events, as compared to percent stenosis as seen on angiography. A ratio greater than 2:1 between the flow in the normal and abnormal arteries is all that is necessary for detecting perfusion defects on pharmacologic stress perfusion scintigraphy. Antianginal medications have no impact on vasodilator pharmacologic stress since they do not interfere with vasodilator induced coronary hyperemia. Exogenous adenosine has a very short half-life (2-10 sec.) and therefore it requires a continuous infusion. The agent produces a mild dose related decrease in systolic and diastolic blood pressure, and a slight increase in heart rate.

Adenosine is a ligand of four distinct cell membrane receptors- A₁, A_2A, A_2B, and A₃ [49]. Adenosine produces coronary vasodilatation via activation of purine A_2A receptors in a dose dependent manner and it produces more consistent and greater coronary vasodilatation than dipyridamole [34]. A_2B receptors are also involved with vasodilatation [49]. A drawback of adenosine (and dipyridamole) is that these agents also non-selectively activate other adenosine receptors (A₁ and A₃) which are associated with undesirable side effects (such as dyspnea, flushing, chest pain, and A-V block [A₁ receptor]) [41,49]. Newer pharmacologic agents have been developed (such as binodenoson and regadenoson) which will more selectively target the A_2A receptor with the hope that these will produce fewer unwanted side effects [41,49].

There is an underlying physiologic basis for why adenosine is so effective in producing coronary artery dilatation. In the setting of myocardial ischemia there is an immediate breakdown of adenosine triphosphate which generates increased circulating levels of adenosine. Adenosine acts to: 1) Produce vasodilatation in an effort to restore flow (dilates coronary arterioles by interacting with A_2A receptors in the outer part of the endothelium and smooth muscle cell membranes) and 2) reduce A-V node transmission to protect the heart from sympathetic overstimulation.

Technique

Patient preparation is similar to that for dipyridamole.

Adenosine produces consistent vasodilatation in most patients at an infusion rate of 140ug/kg/minute for a 4 minute infusion [48]. The shorter infusion appears to be associated with less frequent side-effects, but the extent of the perfusion defect may be smaller than that seen with 6 minute infusions [30]. Maximal vasodilatation is generally observed within 2 minutes of initiation of the infusion. The infusion rate may be reduced to 75-100ug/kg if the patient experiences severe side effects and the response is almost instantaneous. The radiotracer injection is given midway through the infusion (2 minutes for a 4 minute infusion; 3 minutes for a 6 minute infusion). In high risk patients (recent MI, recent unstable angina, borderline hypotension, history of bronchospasm, or CHF), a step-wise increase in infusion rate may be performed. The infusion should begin at 50ug/kg/min. and increase to 75, 100, and 140 ug/kg/min at one minute intervals followed by injection of the tracer one minute after the highest infusion rate. The tracer should always be injected in a separate vein in the other arm to avoid giving a bolus of adenosine when the agent is flushed. Early termination of the infusion should be considered for patients that develop severe hypotension (BP systolic less than 90 mm Hg), wheezing, chest pain associated with ECG evidence of ischemia (ST depression over 2 mm), and in patients that develop persistent second degree or complete heart block. Aminophylline is not necessary to reverse the adenosine due to the extremely short half-life of adenosine (2-10 sec.). ECG and hemodynamic monitoring is generally continued for 8 minutes after termination of the adenosine infusion [48].

Slow walking on a treadmill during the adenosine infusion can: 1- help to decrease splanchnic activity (which may be problematic particularly with the technetium perfusion agents), 2- improve target-to-background ratio, 3- reduce the incidence of minor side effects, and 4- may result in greater ischemia detection than with adenosine alone [19,30,31,48]. Walking is usually done on a 0% grade at 1 mph simultaneous with the adenosine infusion [48]. Walking should not be performed for patients with left bundle branch block or ventricular pacing [48].

Contraindications

Absolute Contraindications:

1- Second/Third Degree AV Block (Unless pacemaker is present)

2- Wheezing or a history of severe Bronchospasm or Asthma: The bronchoconstricting effects of adenosine appear to be concentration dependent and more likely to occur at higher infusion rates (greater than 100 ?g/kg/min) [50]. Patients with stable mild asthma or COPD pre-treated with an inhaled beta-2-agonist may be able to tolerate adenosine stress when the infusion is titrated up to 140 ?g/kg/min over a 6 minute infusion [50]. Patients with mild asthma or COPD should not be currently on corticosteroid therapy, have no wheezing on auscultation at the time of testing, and no admission for an exacerbation during the past year [50]. None-the-less, up to 7% of mild asthma/COPD patients may develop intolerable symptoms necessitating discontinuation of the adenosine infusion and intervention [50]. In general, the bronchospasm resolves within a few minutes of termination of the infusion and administration of inhaled salbutamol [50]. Late bronchoconstriction after discontinuation of the adenosine infusion is unlikely [50].

3- Hypotension (systolic BP less than 90 mmHg)

4- Use of xanthines (caffeine, aminophyllin, theophyllin) or dipyridamole within the preceding 24 hours. Xanthines are competitive inhibitors of adenosine A2 receptors [46]. These agents bind to the receptor, but do not produce vasodilatory effects thereby blunting the effect of adenosine resulting in a false-negative exam [46]. Dipyridamole blocks adenosine transport into cells and may lead to very high blood levels and increased risk of serious side effects. Patients should be off this medication for at least 24 hours. Adenosine induced hyperemia is attenuated by caffeine [34]. The plasma caffeine half-life for healthy subjects is between 4.9 to 5.7 hours and most patients will have a caffeine level of less than 1 mg/L after a 24 hour abstinence [34]. Medications containing dipyridamole or verapamil should be discontinued 48 hours prior to the test [48].

Relative Contraindications:

1- Sick sinus syndrome: These patients may be at an increased risk for developing severe bradycardia.

Side Effects

Side effects are very common and occur in about 80% of patients. Side effects also tend to be more intense than with dipyridamole. Severe adverse effects that require discontinuation of the infusion occur in 5% to 7% of patients. A complete lack of even mild side effects (such as flushing) may raise the possibility of unreported caffeine intake or of faulty adenosine administration [48].

Common, benign effects

Common side effects include decreased blood pressure, increased heart rate, chest pain (35-50%), headache (20-35%), flushing (30-35%), SOB/dyspnea (15%- due to adenosine induced hyperventilation through stimulation of the carotid chemoreceptors). Chest pain is usually atypical and does not correlate with the presence of CAD. Ischemic ECG changes (ST depression) are seen in about 12% of patients and there presence is strong indicator of coronary artery stenosis.

More serious side effects include:

1- Cardiac bradyarrhythmias and heart block

Adenosine slows conduction in the proximal parts of the AV node by stimulating A1 receptors and it also directly inhibits the sinus node conduction. Episodes typically begin within the first 2 minutes of the infusion and generally are very transient, lasting only a few beats. If prolonged, it will typically will resolve in 1 to 2 minutes following discontinuance of the infusion. 1st degree A-V block (10%), 2d (3.6%) or 3d degree block (very rare<1%) have all been described. Adenosine should be used with caution in patients following orthotopic liver transplant due to an increased risk of sinus arrest [43].

2- Bronchospasm

Infusion should be discontinued. Rarely intravenous aminophylline infusion (50-100 mg) is required [48].