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Nonexercise Stress Echocardiography for Diagnosis of Coronary Disease
Stress echocardiography (SE) is a mainstay of ischemic heart disease diagnosis and risk stratification. For diagnosis of coronary artery disease (CAD), various stressors (e.g., exercise, pharmacologic agents, pacing) are used to create an imbalance between oxygen supply and demand, resulting in myocardial ischemia. The induction of ischemia progresses from impaired perfusion and metabolic changes to regional systolic dysfunction (manifesting as wall motion abnormalities [WMAs]), electrocardiographic changes, and symptoms. This sequence of events is known as the ischemic cascade , and regional WMAs are therefore an early, sensitive indicator of ischemia.
Accurate diagnosis of CAD with SE requires a high level of cardiovascular stress. Although exercise is the most physiologic stressor, it is unfeasible or inconclusive in 30% to 40% of patients due to physical limitations (e.g., peripheral vascular disease), deconditioning (i.e., submaximal effort), or an uninterpretable electrocardiogram (ECG). Acquisition of images at peak exercise stress is challenging and requires a high level of expertise to compensate for the image degradation caused by hyperventilation and excessive chest wall motion. Pharmacologic SE is a practical alternative that is widely used for diagnosis and risk stratification of CAD. ,
Detection of myocardial viability in patients with ischemic left ventricular (LV) systolic dysfunction is another indication for SE. Dysfunctional myocardium at rest that has the potential to recover with revascularization usually responds to a low-stress challenge with improvement in regional wall motion (i.e., contractile reserve). In contrast, myocardial segments that remain dysfunctional throughout low-dose stress typically indicate nonviable scar tissue. A biphasic response, characterized by initial improvement of regional function followed by deterioration, can be observed at higher levels of stress when ischemia develops as a consequence of significant stenosis in the setting of an elevated heart rate.
The accuracy of SE relies on adequate visualization of the LV endocardial border, which can be enhanced with contrast media, thereby improving the diagnostic accuracy and prognostic value of SE. This chapter focuses on nonexercise SE techniques, providing an overview of pharmacologic and nonpharmacologic stressors, and the diagnostic accuracy and prognostic value of these techniques. The role of emerging techniques (e.g., three-dimensional [3D] imaging, tissue Doppler imaging [TDI], and strain imaging) in nonexercise SE is discussed.
Stress Echocardiography Suite, Pharmacologic Stressors, And Protocols
Before performing nonexercise SE, informed patient consent should be obtained and contraindications reviewed ( Table 20.1 and Fig. 20.1 ). , The quality of echocardiographic windows should be checked beforehand, and use of intravenous contrast is recommended if two or more endocardial segments cannot be visualized. Nonexercise SE should be performed with ECG (remote from echocardiography windows) and blood pressure monitoring; in a dedicated suite comprising a private room with a height-adjustable bed (with a cutout for apical probe placement), appropriate monitoring facilities (e.g., ECG, blood pressure, pulse oximetry), and resuscitation equipment, including drugs and a defibrillator.
TABLE 20.1
Contraindications to the Use of Pharmacologic Stressors.
| Rationale | Comments | |
|---|---|---|
| General Contraindications | ||
| Anti-ischemic therapy (nitrates, β-blockers, calcium channel antagonists) | Influences the diagnostic and prognostic value of the test | If a stress test is conducted, there is a risk of not achieving the target heart rate (i.e., an inadequate test result may be achieved). |
| Acute coronary syndrome ≤1 week earlier | Risk of cardiac rupture | Stress testing cannot proceed under any circumstances. |
| LV thrombus | Increased cardiac deformation during stress may dislodge the thrombus | Stress testing cannot proceed under any circumstances. |
| Recent pulmonary embolism | Cardiac decompensation due to stress | Stress testing cannot proceed under any circumstances. |
| Recent aortic dissection | Progression due to increased blood pressure during stress | Stress testing cannot proceed under any circumstances. |
| Decompensated LV failure | Further decompensation due to stress | Stress testing cannot proceed under any circumstances. |
| Active endocarditis, myocarditis, or pericarditis | Progression of disease | — |
| Contraindications to Dobutamine | ||
| Uncontrolled or poorly controlled systemic hypertension | Increase of blood pressure with dobutamine stress | Vasodilator (dipyridamole) stress testing can be considered—no significant hypertensive response. |
| History of (serious) arrhythmias | Precipitation of arrhythmias with dobutamine stress | Vasodilator (dipyridamole) stress testing can be considered—no significant arrhythmic risk. |
| LV outflow tract obstruction or hypertrophic cardiomyopathy | Peripheral vasodilatation, with increased outflow tract gradient | — |
| Severe aortic stenosis | Peripheral vasodilatation, with increased outflow tract gradient | Dobutamine stress echocardiography has a role in low-flow, low-gradient aortic stenosis. |
| Hypokalemia | Potentiates risk of ventricular arrhythmias | Investigate the cause before administration of dobutamine. |
| Contraindications to Atropine | ||
| Closed-angle glaucoma | Precipitation of acute angle closure glaucoma by mydriasis | — |
| Benign prostatic hyperplasia | Precipitation of acute urinary retention by parasympatholytic effect on detrusor muscle | — |
| Contraindications to Vasodilators | ||
| Reactive airways disease | Acute reactivity of airways could be precipitated or worsened by vasodilators | Regadenoson is an alternative. Dobutamine is another option. |
| Recent xanthine use (<12 h earlier) or caffeine ingestion | Methylxanthines antagonize the effects of vasodilators | Can continue with dobutamine as stressor. |
| Advanced atrioventricular block (second or third degree) | Potentiation of atrioventricular block by vasodilators | Dobutamine is an alternative. |
| Sinus node dysfunction | Decrease in spontaneous depolarization of sinoatrial node with vasodilators, leading to potentially severe bradycardia | — |
| Wolff-Parkinson-White syndrome | Atrioventricular block with vasodilators, allowing conduction through an accessory pathway | — |
| Carotid artery stenosis | Cerebral ischemia or infarction due to hypoperfusion | — |
Stressors (e.g., dobutamine, dipyridamole) are administered through an intravenous cannula into an antecubital vein. If possible, a medial antecubital vein is preferred because it drains directly through the basilic vein into the axillary vein, whereas use of a lateral antecubital vein may cause a delay in effect (and unpredictable pharmacokinetics) of infused drugs at the entry of the cephalic vein into the axillary vein, where a valve is often found. A three-way stopcock is advisable for administering adjunctive atropine or intravenous contrast medium. A 12-lead ECG is recorded at baseline and at 1-minute intervals (while being continuously displayed on the echocardiography monitor throughout the examination) to detect ischemic changes or arrhythmias. Sphygmomanometric blood pressure readings are obtained at baseline and during each protocol stage.
With the patient in a left lateral decubitus position, echocardiographic data are optimized and acquired at baseline and at each stage (i.e., baseline, low dose, peak dose, and recovery) of the protocol, typically including parasternal long- and short-axis views, apical 4- and 2-chamber views, and a long-axis view. A minimum of three RR intervals should be saved for every view in every stage of the protocol to allow meaningful interpretation.
The definition of low-dose and peak-dose stages and image sets depends on the clinical question, the stressor used, and the patient’s response. If viability testing is performed with dobutamine, low-dose images are acquired at an infusion rate of 5 μg/kg per minute, in contrast to ischemia testing, in which the low-dose stage reflects the myocardial response at 10 μg/kg per minute. Dipyridamole low-dose images are obtained after a dose of 0.56 mg/kg has been administered. Peak-dose images are acquired when 85% of the target heart rate is achieved by dobutamine (with or without atropine) stress or after the total dipyridamole dose of 0.84 mg/kg has been administered. Recovery images are taken after administration of the stressor has been terminated (i.e., after 3 minutes or when the peak heart rate has decreased by 10–20 beats/min).
The echocardiography machine reproduces baseline settings for each stage and view of the protocol, simplifying acquisition but also mandating attention to the baseline settings, which are reproduced automatically for every stage. To allow comparative analysis of a single view in various stages, a quad-screen format is required.
Segmental wall motion is reported according to the terminology in Table 20.2 . A distinction is made between active inward motion and tethering, the latter referring to passive motion of a segment due to forces exerted on it by adjacent myocardium. Tethering can be difficult to distinguish visually from active motion. However, decreased myocardial thickening reflects true contractility, and it is therefore a more specific sign of abnormal myocardial wall motion. Ventricular dyssynchrony (e.g., due to an RV pacemaker, bundle branch block, or post-surgical status) can mimic abnormal wall motion, but careful assessment of wall thickening can distinguish it from true WMAs.
TABLE 20.2
Wall Motion Terminology and Qualitative Analysis of Wall Motion at Rest and Peak Stress, Correlated With Underlying Pathophysiology.
| Wall Motion Terminology | ||
|---|---|---|
| Term | Definition | |
| Normokinesia | Normal inward motion/thickening | |
| Hypokinesia | Reduced inward motion/thickening Hypokinesia is sometimes defined in more detail as (1) reduced amplitude of endocardial motion, (2) reduced velocity of endocardial motion, (3) reduced systolic wall thickening, or (4) delay in onset of segmental motion (tardokinesia) |
|
| Akinesia | Absent inward motion/thickening | |
| Dyskinesia | Systolic outward motion | |
| Qualitative Analysis of Wall Motion Correlated With Underlying Pathophysiology | ||
|---|---|---|
| Pathophysiology | Rest | Stress |
| Normal | Normokinesia | Normokinesia, hyperkinesia |
| Ischemia | Normokinesia | Hypokinesia, akinesia, dyskinesia |
| Viable | Hypokinesia, akinesia | Hypokinesia, normokinesia |
| Nonviable scar | Akinesia, dyskinesia | Akinesia, dyskinesia |
Localization of WMAs is performed using a 16- or 17-segment model of the LV, according to the coronary artery territory ( Fig. 20.2 and 
). The anatomic variation among individuals in the myocardial territories supplied by the various coronary arteries should be considered.
Diagnostic end points of pharmacologic SE include (1) administration of the maximum dose of stressor, (2) achievement of the target heart rate ([220 − age in years] × 0.85), (3) new WMAs in at least two contiguous LV segments, and (4) angina and ECG changes indicative of ischemia (>2 mm changes in the ST segment of two contiguous leads ( Fig. 20.3 ). Nondiagnostic end points include intolerable symptoms, hypertension (systolic blood pressure >220 mmHg or diastolic blood pressure >120 mmHg), hypotension (>40 mmHg drop), supraventricular and ventricular arrhythmias, and polymorphic ventricular beats.
If cardiac arrest or life-threatening arrhythmias occur, resuscitation should proceed according to published guidelines such as those proposed by the European Resuscitation Council. The test is concluded when (1) the heart rate has decreased to within 20 beats/min of baseline, and (2) all new WMAs have resolved. The patient is transferred to a recovery area, and the intravenous cannula is left in situ in case of a delayed contrast reaction. The report is subsequently written, including all relevant clinical information ( Table 20.3 ).
TABLE 20.3
Recommendations for Components of a Standard Stress Echocardiography Report.
| Component | Text | ||||
|---|---|---|---|---|---|
| Patient details | Name, surname, age, gender, date, hospital number, referring clinician, operator(s) | ||||
| Clinical background | Known coronary artery disease? Previous myocardial revascularization? Inability to complete exercise? |
||||
| Indication for test | Evaluation of inducible ischemia or viability | ||||
| HR (beats/min) | BP (mmHg) | Heart Rhythm | New WMA | Symptoms | |
|---|---|---|---|---|---|
| Baseline | … | …/… | SR/AF/VT | Yes/No | Yes/No |
| Low dose | … | …/… | SR/AF/VT | Yes/No | Yes/No |
| Peak dose | … | …/… | SR/AF/VT | Yes/No | Yes/No |
| Recovery | … | …/… | SR/AF/VT | Yes/No | Yes/No |
| Baseline imaging | LV systolic function and wall motion analysis at rest. | ||||
| Low-dose imaging | Dose of dobutamine infusion rate (5 or 10 μg/kg per minute). Describe changes in LV wall motion analysis. | ||||
| Peak-dose imaging | Dose of dobutamine infusion rate (maximum 40 μg/kg per minute) and dose of atropine if added. Describe changes in LV wall motion analysis. | ||||
| Recovery phase | Indicate whether β-blockers were used. Describe changes in LV wall motion analysis. | ||||
| Summary/conclusions | The test is positive/negative for ischemia/viability. | ||||
AF , Atrial fibrillation; BP , blood pressure; HR, heart rate; SR , sinus rhythm; VT , ventricular tachycardia; WMA , wall motion abnormality.
Dobutamine and Atropine Stress Echocardiography
Dobutamine is a racemic mixture of the levo-isomer (α 1 -agonist) and the dextro-isomer (α 1 -antagonist) and has only weak α-effects as a result. Both isomers are β-receptor agonists, having higher affinity for β 1 - than β 2 -receptors. Myocardial demand ischemia is provoked by an increase in myocardial contractility due to inotropy (β 1 -receptors) at lower doses and by an increase in heart rate due to reflex tachycardia from peripheral vasodilation (β 2 -receptors) at higher doses and, to a lesser extent, chronotropy (β 1 -receptors) at lower doses ( Fig. 20.4 ). Secondary mechanisms of ischemia include greater oxygen demand due to cellular effects (e.g., inefficient excitation-contraction coupling); this is referred to as an oxygen-wasting effect .
For myocardial ischemia detection, dobutamine SE is performed with a continuous intravenous infusion (half-life [t 1/2 ] of <2 min), starting at 5 μg/kg per minute and increasing every 3 to 5 minutes by 10 μg/kg per minute until a dose of 40 μg/kg per minute or a diagnostic end point is reached (see Summary table). If the target heart rate is not achieved with a maximal dobutamine dose (e.g., due to a reflex bradycardia in response to hypertension), the maximal rate (40 μg/kg per minute) is maintained while intravenous atropine sulfate is administered, starting with a 0.25-mg atropine bolus and increasing to a maximum of 2 mg.
Atropine is an anticholinergic agent that binds to vagal muscarinic acetylcholine receptors. Its parasympatholytic effect is mediated by inhibition of the sinoatrial and atrioventricular (AV) nodes, which causes a chronotropic and enhanced dromotropic effect and subsequent tachycardia ( Fig. 20.5 ). For myocardial viability assessment, a low-dose dobutamine protocol (maximum dose, 10 μg/kg per minute) is used.
The pharmacodynamic effects of dobutamine and atropine can be counteracted by an intravenous β-blocker (e.g., esmolol 0.5 mg/kg bolus followed by 0.2 mg/kg boluses titrated to heart rate). This may be used to ameliorate unwanted effects (e.g., ischemia) or to shorten the recovery phase (especially when atropine has been administered because its t 1/2 is longer than that of dobutamine).
Serious unwanted effects of dobutamine include myocardial ischemia, severe hypertension (which also decreases specificity because regional WMAs may reflect the increased afterload rather than ischemia), life-threatening arrhythmias, and death (3 per 1000 patients). Less severe effects include palpitations, atrial tachyarrhythmias, premature ventricular complexes, urinary urgency, anxiety (potentiated by atropine), nausea, and hypotension. Hypotension is primarily a consequence of the vasodilator effect of high-dose dobutamine, although loss of synchronized AV contraction (due to atrial arrhythmias), LV outflow tract obstruction, and ischemia can also contribute.
Dipyridamole, Adenosine, And Regadenoson Stress Echocardiography
Dipyridamole is a vasodilator that acts indirectly by inhibition of (1) adenosine degradation (by adenosine deaminase) and (2) adenosine reuptake by cardiomyocytes. Increased adenosine concentrations act on adenosine A 1 , A 2A , A 2B , and A 3 receptors. Coronary vasodilation is mediated by A 2A receptors on smooth muscle cells of coronary resistance vessels (<400 μm), whereas stimulation of A 1 , A 2B , and A 3 receptors cause AV conduction block and bronchoconstriction ( Fig. 20.6 ).
Myocardial ischemia detection using dipyridamole relies on the induction of a steal phenomenon. Preferential vasodilation occurs in myocardial territories subtended by nonobstructed coronary arteries, resulting in a redistribution of blood flow toward nonischemic areas and away from ischemic zones. Collaterals also play a role in the redistribution of blood flow. This is known as horizontal steal (see Fig. 20.6 ). Vertical steal also occurs with vasodilator stress; it refers to a decrease in perfusion across a significant epicardial coronary stenosis when the distal pressure is decreased beyond the point at which distal flow can be increased (see Fig. 20.6 ). Secondary mechanisms are a reflex tachycardia that occurs in response to systemic hypotension and increasing oxygen consumption. Patients should refrain from ingesting methylxanthines (e.g., prescription drugs, food, beverages) for at least 12 hours before dipyridamole (or adenosine) stress testing because they are competitive antagonists of adenosine receptors.
Dipyridamole SE consists of an intravenous infusion of 0.84 mg/kg over 10 minutes in two stages: 0.56 mg/kg administered over 4 minutes and, after 4 additional minutes, 0.28 mg/kg over 2 minutes (see Summary table). A protocol administering the total dose of 0.84 mg/kg over 6 minutes increases the sensitivity of the test. If no end point is reached, atropine (0.25-mg boluses, up to a maximum of 2 mg) can be added. The protocol for use of adenosine is to administer 100 μg/kg per minute for 3 minutes, followed by 140 μg/kg per minute for another 4 minutes, and then increased to a maximum of 200 μg/kg per minute for 4 minutes (see Summary table).
Vasodilator-related side effects include flushing, headache, bronchospasm, complete AV block, cerebral hypoperfusion (in the setting of carotid artery stenosis), nonischemic chest pain from direct stimulation of nociceptors, and ischemic chest pain. Because of the indirect mechanism of action of dipyridamole, its onset of action is slower than that of adenosine, and its unwanted effects are less severe but of longer duration.
Vasodilators are contraindicated in the setting of reactive airways disease or preexisting AV block. Regadenoson is a selective A 2A adenosine receptor agonist with a rapid onset of action ( t 1/2 = 3 minutes) (see Summary table). , It can be used safely in patients with mild or moderate reactive airways disease, and 400 μg is administered over 10 seconds. The effects of dipyridamole, adenosine, and regadenoson can be antagonized with slow intravenous administration of aminophylline (50 mg boluses titrated up to a maximum dose of 250 mg). In the case of adenosine, because of its very short t 1/2 , cessation of the infusion usually suffices to treat unwanted effects.
Ergonovine Stress Echocardiography
Ergonovine is an ergot alkaloid that precipitates coronary vasospasm by stimulation of serotonergic (5-HT2) receptors on vascular smooth muscle. It can be used to diagnose vasospastic angina (i.e., Prinzmetal angina) noninvasively with echocardiography. A sensitivity of 91% and a specificity of 88% have been reported with the following protocol: a 50-μg intravenous bolus of ergonovine maleate every 5 minutes until myocardial ischemia (i.e., WMA) is detected or until the maximum dose of 0.35 mg is reached. , The action of ergonovine can be antagonized by intravenous nitroglycerin (0.25 mg), sublingual nitroglycerin (0.6 mg), or sublingual nifedipine (10 mg).
Pacing Stress Echocardiography
If the target heart rate cannot be achieved with pharmacologic stress alone, the pacing rate can be increased by external programming. If pacing SE is used without a pharmacologic stressor, a suggested protocol is to increase the pacing rate, commencing at 110 beats/min, by 10 beats/min every 2 minutes until the target heart rate is reached or an alternative end point has been achieved. Because RV pacing causes dyssynchronous ventricular contractions, which may simulate regional WMAs, atrial or biventricular pacing is preferred. Regional wall thickening can be still evaluated.
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