Introduction
Over many decades, echocardiography has evolved considerably to provide a comprehensive assessment of cardiac structure and function in a truly bedside manner. Echocardiography is a readily available technique that is portable, inexpensive, and free from radiation. Echocardiographic imaging modalities now include M-mode, two-dimensional, flow Doppler, color flow mapping, tissue Doppler, contrast, three-dimensional, and speckle-tracking strain imaging. Echocardiography may also be applied in conjunction with exercise or pharmacologic stress in the diagnostic evaluation of coronary artery disease (CAD) and for certain noncoronary conditions. In addition, echocardiography may be performed via the transesophageal route, not only for diagnostic purposes, but increasingly for imaging guidance during cardiac structural interventions under general anaesthesia. Consequently, the indications for echocardiography are wide ranging, leading to the publication of numerous international guidelines for standardization of methodologies and appropriate use of the technique in various cardiac conditions.
In this chapter, the clinical application of echocardiography will be divided into three broad categories as follows: (1) detection of CAD, (2) assessment of left ventricular (LV) dysfunction, and (3) delineation of structural complications.
Detection of Coronary Artery Disease
Pathophysiology of Myocardial Ischemia
The pathophysiologic changes that occur as a consequence of interruption in coronary blood flow are described by the ischemic cascade as shown in Fig. 11.1 . Resting blood flow may be preserved until a coronary artery stenosis approaches 90% diameter narrowing. At lesser degrees of stenosis, although resting flow is normal, coronary flow reserve (CFR) may be reduced such that when there is an increase in oxygen demand with exercise, there is an inability to increase blood flow adequately to meet the metabolic requirements, leading to a supply-demand mismatch and subsequent myocardial ischemia. The inadequate increase in blood flow in the stenosed coronary artery bed leads to a sequential reduction in myocardial perfusion, diastolic dysfunction, reduced myocardial systolic strain, visible regional wall motion abnormality (WMA), electrocardiogram (ECG) changes, and finally symptoms. These changes are reversible with cessation of exercise. In addition to coronary artery stenosis severity, blood flow to the myocardium may be affected by location of the stenosis, lesion length, number of lesions, and comorbidities such as hypertension and diabetes affecting intrinsic CFR.
Regional Wall Motion Changes in Myocardial Ischemia and Infarction
The echocardiographic hallmark of underlying CAD is the presence of resting or stress-induced regional WMA. Normal LV wall motion consists of endocardial thickening that occurs in a relatively synchronous manner in all myocardial walls leading to a decrease in cavity size. These changes are greater in magnitude at the base of the LV and less so moving toward the apex. Normal myocardial contraction depends predominantly on endocardial rather than epicardial contraction because the velocity and magnitude of contraction are greater in the subendocardial rather than subepicardial layers. Consequently, impaired function of the subendocardial muscle fibers has a disproportionate impact on overall wall thickening and LV systolic function. It has been shown that ischemia or infarction of the inner 20% of the myocardial wall leads to an absence of visible contraction in that region. This means that even nontransmural ischemia or infarction results in malfunction of the entire wall that is indistinguishable from that seen with transmural involvement.
If a prolonged period of ischemia has occurred due to transient occlusion with minimal infarction and restoration of blood flow, recovery of function within the affected myocardial segment may be delayed due to myocardial stunning. Repetitive episodes of demand ischemia may also lead to myocardial stunning. Echocardiographically, myocardial stunning manifests as a persistent regional WMA soon after restoration of blood flow, followed by recovery of contraction within a few days up to a few weeks later.
If complete coronary artery occlusion occurs and flow is not restored, myocardial infarction (MI) and necrosis may ensue leading to persistent regional WMA and LV dysfunction. The extent of myocardial damage depends on the duration of complete coronary artery occlusion. If flow can be restored within 60 minutes, myocardial loss may be minimized. If flow can be restored within 4 hours there may be varying degrees of nontransmural or partial thickness infarction involving the subendocardial layers. A complete absence of blood flow for 4 to 6 hours tends to result in irreversible, transmural myocardial damage. The location of the regional WMA is a good indicator of the coronary artery territory involved in the infarction. However, the size of the WMA on echocardiography may overestimate infarct size both in terms of thickness of infarction due to tethering of the adjacent noninfarcted walls.
In some patients with LV dysfunction due to CAD, there may be areas of chronically dysfunctional myocardium that result from a state of chronic low blood flow, enough to sustain viability to the affected myocardium, but causing repetitive ischemia and stunning. These areas of so-called hibernating myocardium have the ability to regain contractile function following revascularization and are therefore important to identify.
Resting Echocardiography
A resting echocardiogram may be helpful in the diagnosis of CAD if performed during symptoms. If a WMA is identified during chest pain and then resolves with relief of symptoms, this is very good evidence that the chest pain is due to myocardial ischemia. Equally, even in the absence of symptoms, the detection of a regional area of akinesia at rest is suggestive of silent CAD and previous MI, particularly if associated with increased echogenicity and thinning of the myocardium ( ). In the absence of symptoms, a normal resting echocardiogram adds little in establishing whether the patient has underlying CAD. Importantly, however, there are a number of other cardiac causes of chest pain, such as severe aortic stenosis, hypertrophic cardiomyopathy, mitral valve prolapse, and right ventricular pathology which may be excluded by echocardiography. Transthoracic echocardiography may also be useful in the evaluation of chest pain in the acute setting for differentiating MI, aortic dissection, pulmonary embolism, or acute pericarditis and pericardial effusion.
Stress Echocardiography
In view of the limited diagnostic accuracy of exercise electrocardiography, cardiac imaging-based investigations are gradually superseding its use in clinical practice. Moreover, approximately 20% to 30% of patients are unable to exercise adequately because of comorbidities such as osteoarthritis, chronic pulmonary disease, and peripheral vascular disease.
The technique of stress echocardiography became clinically applicable in the 1980s when two-dimensional echocardiography was used in conjunction with physiologic exercise or pharmacologic stress agents to provoke ischemia. Since then, with continued technological advances in image quality, particularly the introduction of intravenous ultrasound contrast agents, stress echocardiography has evolved into a safe, accurate, and well-established technique for the diagnostic and prognostic evaluation of suspected cardiac chest pain.
Exercise Echocardiography
Physiologic exercise is the preferred method of stress testing for ambulant patients, and this can be achieved either by treadmill exercise or bicycle ergometry. For treadmill exercise, the Bruce protocol is most commonly used and the exercise time or workload achieved per se provides useful clinical and prognostic information. Imaging under these circumstances is performed at rest and immediately after exercise, allowing a time interval of approximately 60 to 90 seconds in which to acquire the poststress images. Upright or semisupine bicycle ergometry offers the advantage of imaging at any time during exercise, rather than immediately postexercise as with treadmill exercise. However, the test may be limited by suboptimal patient position for image acquisition or leg fatigue preventing the attainment of target heart rate and potential cardiac symptoms. Treadmill exercise tends to evoke a higher workload and peak heart rate than does bicycle ergometry and therefore may be preferable for ischemia testing. However, bicycle exercise may be more suitable if additional Doppler-derived information is required, for example, on valve function, filling pressures, or pulmonary artery (PA) pressure.
Pharmacologic Stress Echocardiography
A pharmacologic approach to stress testing, using inotropic or vasodilator stress agents in conjunction with echocardiography, is a suitable alternative for those unable to exercise and provides similar diagnostic accuracy to exercise echocardiography. Pharmacologic stress testing avoids the challenges of image acquisition posed by exercise such as hyperventilation and excessive chest wall movement. Moreover, the stress images can be obtained at a constant and controlled heart rate at peak stress without undue time pressure.
1
Dobutamine Stress Echocardiography
Dobutamine, a synthetic catecholamine, is the most widely used stressor agent and acts by stimulating α-1, β-1, and β-2 adrenoceptors. This leads to an increase in heart rate, blood pressure (BP), and inotropic activity, thereby increasing myocardial oxygen demand. The protocol for dobutamine stress echocardiography uses a weight-adjusted, graded intravenous dobutamine infusion ( Fig. 11.2 ). Echocardiographic images are acquired at rest, mid-dose, peak dose, and recovery; heart rate, BP, and cardiac rhythm are monitored throughout the study. The increase in systolic BP is less with dobutamine compared to exercise. Endpoints of the test include achievement of 85% of age-predicted target heart rate; development of cardiac symptoms or ischemia, arrhythmias, hypotension, or severe hypertension; and intolerable side effects to dobutamine. If target heart rate has not been achieved at maximal dobutamine stress, intravenous atropine may be given in divided doses to a maximum dose of 2 mg. On rare occasions, short-acting intravenous β-blockade may be needed to reverse the effects of dobutamine.
Achievement of target heart rate is an important goal of ischemia testing with dobutamine, and therefore any rate-limiting medications should be withheld for at least 48 hours to avoid a nondiagnostic test. Among those with reportedly normal dobutamine stress echocardiograms, a suboptimal heart rate response is associated with a higher cardiac event rate.
The use of dobutamine is associated with side effects such as headache, tremor, palpitations, nausea, urinary urgency, and anxiety, but with prior counselling and reassurance these are adequately well tolerated and do not usually lead to premature termination of the test. A minority of patients develop a reflex vagal response to dobutamine leading to hypotension and a fall in heart rate. Every test carries a definite, albeit minor, risk and exercise is generally safer than pharmacologic stress. For dobutamine stress echocardiography, ventricular arrhythmias, prolonged ischemia, and MI have a reported incidence of approximately 1 in 1000 with an incidence of death of 1 in 5000. In experienced hands, dobutamine stress echocardiography can be safely performed in patients with LV dysfunction, aortic and cerebral aneurysms, and implantable cardioverter defibrillators.
2
Vasodilator Stress Echocardiography
Vasodilator stress echocardiography is typically performed with either dipyridamole or adenosine. Dipyridamole stimulates A 2A adenosinergic receptors present on the endothelial and smooth muscle cells of coronary arterioles. This leads to an increase in endogenous adenosine levels by the inhibition of cellular uptake of adenosine and the prevention of its breakdown by adenosine deaminase. Adenosine is a coronary arteriolar vasodilator that causes hyperemia in myocardial segments with normal vasodilatory reserve, ie, without significant epicardial stenoses or impairment in microvascular function. In contrast, segments with impaired vasodilatory reserve may become ischemic after administration of adenosine, due to a coronary steal phenomenon, where blood flow is preferentially directed to segments with normal epicardial and microvascular resistance ( e-Figs. 11.1 and 11.2 ).
The dipyridamole protocol consists of an intravenous infusion of 0.84 mg/kg over 10 min, in two separate doses. A dose of 0.56 mg/kg is given over 4 min, followed by echocardiographic imaging, and if no sign of ischemia, an additional 0.28 mg/kg is given over 2 min. If no endpoint is reached, atropine is added. The same overall dose of 0.84 mg/kg can also be given over 6 min. All caffeine-containing foods should be avoided for 12 hours before testing, and all theophylline-containing drugs should be discontinued for at least 24 hours. The peak vasodilatory effect of dipyridamole is obtained 4 to 8 minutes after the end of the infusion, and the half-life is approximately 6 hours. The dipyridamole dose usually employed for stress echocardiography (0.84 mg/kg) causes a 3- to 4-fold increase in coronary blood flow in normals over resting values. Vasodilator stress usually produces a mild decrease in BP and a mild increase in heart rate. Therefore, atropine is frequently required to achieve target heart rate and thereby increase myocardial oxygen demand. Aminophylline should be available for immediate use in case an adverse dipyridamole-related event occurs and be routinely infused at the end of the test.
Adenosine can be used in a similar manner and is typically infused at a maximum dose of 140 μg/kg per min over 6 min. Imaging is performed prior to and after starting the adenosine infusion, and, compared with dipyridamole, adenosine has the advantage of a shorter half-life.
Combined with wall motion assessment, dedicated imaging of the left anterior descending (LAD) coronary artery during vasodilator stress may be performed to provide an assessment of CFR ( e-Fig. 11.3 ). The ratio of hyperemic peak to basal peak diastolic coronary flow Doppler velocities represents CFR, and this parameter has been shown to provide additive prognostic value over and above wall motion assessment. However, the technique is not widely used because of protocol complexity and challenging imaging of the LAD.
Minor, but limiting, side effects preclude the achievement of maximal pharmacologic stress in less than 5% of patients given dipyridamole. Approximately two-thirds of patients studied with the high-dose dipyridamole protocol experience minor side effects such as flushing and headache that usually resolve following administration of aminophylline at the end of testing. On rare occasions, dipyridamole-induced ischemia requires the administration of nitrates. Major life-threatening complications, including MI, complete heart block, asystole, ventricular tachycardia, or pulmonary edema, occur in approximately 1 in 1000 cases. Adenosine has a similar side-effect profile to dipyridamole, but may be safer because of the shorter duration of action. Both agents are contraindicated in patients with significant conduction disease and reactive airways obstruction. Under these circumstances, dobutamine may be the pharmacologic stressor agent of choice. Conversely, vasodilator stress may be a safer option in those with a predisposition to atrial or ventricular tachyarrhythmias. In general, the choice of pharmacologic stressor agent is governed by operator preference and familiarity.
3
Pacing-Induced Stress Echocardiography
In those with a permanent pacemaker, it may not be possible to provoke an adequate heart rate response with exercise or dobutamine-atropine stress. Stress testing can be performed by programming the pacing rate to increase every 2 to 3 minutes until target heart rate is achieved. This technique can be used in conjunction with dobutamine to further increase inotropic activity and myocardial oxygen consumption. Transesophageal atrial pacing stress echocardiography is an alternative method to exercise or pharmacologic stress testing, but has not gained popularity.
Analysis of Regional Wall Motion
Most commonly, analysis of regional wall motion is qualitative, based on visual assessment of myocardial thickening rather than motion, which may be influenced by pushing and pulling forces. Normal wall motion consists mainly of endocardial thickening representing a 35% to 40% increase in wall thickness from diastole with varying reductions in endocardial thickening seen in ischemia. The analysis is aided by dividing the LV into myocardial segments. For the purposes of wall motion analysis, a 16-segment model was previously used, but a 17-segment model is now recommended in which the additional segment represents the true apex. This allows comparison with myocardial perfusion studies using nuclear imaging and cardiac magnetic resonance (CMR) imaging, which have traditionally included a true apical segment. ( Fig. 11.3 ). A visual assessment of each individual segment is made in multiple views, ascribing a wall motion score such that normokinesis = 1, hypokinesis = 2, akinesis = 3, and dyskinesis = 4. The total score of the segments can then be divided by the number of segments analyzed to derive a wall motion score index. A completely normal LV at rest has a score index of 1.0. In the context of previous MI, the wall motion score index at rest provides a very good approximation of the location and size of MI and global LV systolic function. With normal resting wall motion and stress-induced reversible ischemia, the wall motion score index during stress represents the location, extent, and severity of ischemia. This approach helps to identify the coronary artery territory responsible for the regional WMA. Involvement of the anterior septum and anterior wall signifies disease in the LAD artery and its branches ( ), whereas abnormalities of the inferior wall tend to indicate right CAD in the majority of cases ( ). There can be substantial overlap in blood supply to the inferolateral wall by the right coronary and left circumflex arteries, and similarly with the anterolateral walls by the LAD and left circumflex arteries. Dilatation of the LV cavity with stress often indicates multivessel disease ( ). The ischemic threshold may also be assessed by determining the heart rate at which regional WMAs were detected, and this has been shown to correlate with the number of stenosed coronary arteries.
The use of ultrasound contrast agents has helped to improve image quality and observer variability (see following discussion). Most studies are unequivocally negative or positive, but there are sometimes borderline cases in which the image quality is suboptimal or wall motion changes are subtle and of uncertain significance. The most important factor in minimizing variability and maintaining diagnostic accuracy is appropriate and rigorous training in stress echocardiography.
Quantitative methods have been sought to make the findings more tangible and improve reporting by less experienced physicians. Automated endocardial border detection using integrated back scatter, tissue Doppler assessment of myocardial displacement, velocity, strain and strain rate, and real-time three-dimensional imaging have been studied but require further simplification and validation in order to gain clinical acceptance.
Indications
The indications for stress echocardiography are summarized in Box 11.1 . Appropriateness criteria for stress echocardiography have also been established. Dobutamine stress echocardiography is indicated for the assessment of myocardial viability in those with resting akinetic regions, as discussed later.
Universal Indications
Intermediate pretest probability of CAD
Abnormal resting ECG (ST/T wave changes, LBBB)
Inconclusive exercise ECG because of equivocal ST changes
Suspicion of a false-positive exercise ECG
Functional assessment of an equivocal coronary artery stenosis
Evaluation of cardiac etiology of exertional dyspnea
Risk stratification in known CAD
Preoperative risk assessment for noncardiac surgery
Pharmacologic Stress Indications
Inability to exercise
Submaximal exercise ECG
Assessment of myocardial viability—dobutamine
CAD , Coronary artery disease; ECG , electrocardiogram; LBBB , left bundle branch block.
Safety and Feasibility
Advances in imaging technology, in particular the introduction of harmonic imaging and use of ultrasound contrast agents, have significantly improved endocardial definition ( Fig. 11.4 ). Accordingly, stress echocardiography is now feasible in over 95% of patients including those with morbid obesity.
Diagnostic Accuracy
A large evidence base shows that all forms of exercise and pharmacologic stress echocardiography are more accurate than the treadmill exercise ECG, with sensitivities, specificities, and overall diagnostic accuracies approximating to 80% to 90%. The normalcy rate of stress echocardiography is approximately 90% to 95%.
False-negative studies may be due to suboptimal stress, use of β-blockers, single-vessel disease, and hyperdynamic states. False-positive studies can be due to reduced CFR and ischemia in the absence of epicardial CAD. This may include patients with significant LV hypertrophy, diabetes mellitus, myocarditis, cardiomyopathies, and syndrome X. Exercise may result in worsening regional and global systolic function in myopathic ventricles in the absence of ischemia ( ). Abnormal septal motion due to left bundle branch block (LBBB), ventricular pacing, or following cardiac surgery may also confound the interpretation of regional wall changes with stress. In addition, septal dyssynchrony may lead to worsening septal perfusion and wall thickening at higher heart rates in the absence of coronary artery obstruction.
Prognostic Value
Stress echocardiography provides independent prognostic information over and above clinical risk factors and stress test parameters for the prediction of all-cause mortality, cardiac death, and composite endpoints ( e-Fig. 11.4 ). A normal stress echocardiogram yields an annual event rate of less than 1%, similar to that of an age- and sex-matched normal population. Under these circumstances, further diagnostic evaluation is rarely needed and, in particular, coronary angiography can be avoided. A positive stress echocardiogram carries a risk of nonfatal MI and all-cause death over subsequent years of over 10%, and certain stress echo parameters help to further stratify risk. These include the location, extent, and severity of stress-induced WMA, low ischemic threshold, LV hypertrophy, resting ejection fraction (EF), and peak wall motion score index. False-positive stress echocardiograms have also been associated with a higher risk of events, indicating the limitations of coronary angiography as a gold standard.
Cost-Effectiveness Versus Exercise Electrocardiography
Compared to exercise electrocardiography, stress echocardiography identifies more patients as low risk and fewer as intermediate and high risk. Although initial procedural costs are greater, stress echocardiography leads to a lower cost of additional downstream procedures when compared with exercise electrocardiography, with lower rates of coronary angiography and revascularization. Consequently, exercise echocardiography has been shown to be a cost-effective alternative to exercise electrocardiography. Similar results have been shown in patients presenting with troponin-negative chest pain ( e-Fig. 11.5 ).
Comparison with Alternative Imaging Techniques
Perfusion scintigraphy is a long-established technique for ischemia testing and is the main diagnostic alternative to stress echocardiography. The overall diagnostic accuracies of the two techniques and prognostic value are similar; there is a nonsignificant trend toward higher sensitivity with perfusion scintigraphy, but higher specificity with stress echocardiography. The two techniques have broadly similar clinical applications and the choice of test depends mainly on availability and expertise. Although stress echocardiography is operator dependent and more subjective, it has the benefits of lower cost, widely available equipment, truly bedside nature, and no exposure to radiation. In contrast with radionuclide imaging, echocardiographic images can be obtained anywhere along the continuum from rest to peak physiologic stress. Moreover, stress echocardiography has the major advantage of excluding other causes of cardiac symptoms such as valvular disease, cardiomyopathies, pericardial disease, and congenital heart defects. CMR imaging allows the assessment of myocardial perfusion or wall motion with good accuracy. The advantages of the technique are related to high image quality and the absence of ionizing radiation. However, the high costs, lengthy image acquisition, and low availability make CMR a good option mainly when stress echocardiography is nondiagnostic or not feasible. Computed tomography (CT) coronary angiography and coronary calcification scoring is the latest technique to enter the field of cardiac imaging. CT has the inherent limitations of radiation exposure, and more fundamentally, provides anatomic rather than functional information. Nevertheless, as with the other imaging techniques, its use has been advocated in patients with an intermediate pretest probability of CAD.
Contrast Echocardiography for Left Ventricular Opacification
Despite the advances in two-dimensional image quality with harmonic imaging, a significant minority of patients may have suboptimal images. This is particularly notable in patients with obesity, lung disease, or in the intensive care setting. Moreover, the need for very good endocardial definition is paramount in stress echocardiography. These concerns have prompted the development of ultrasound contrast agents to opacify the left ventricle. Since the 1990s, stabilized microbubble ultrasound contrast agents that are capable of transit through the pulmonary circulation have become available. These have been coupled with modifications in ultrasound technology to improve visualization of the microbubbles in the LV cavity and myocardium.
Ultrasound Contrast Agents
Ultrasound contrast agents consist of acoustically active gas–filled microspheres designed to increase the signal strength of ultrasound waves. The microbubbles are smaller than the capillaries in the lungs allowing transit from the venous to the arterial side of the circulation. As they remain intravascular at all times, they act as red blood cell tracers. To prevent dissolution of the microbubble, a low-solubility, high-molecular-weight gas is used. The microbubbles are stabilized by the outer shell coated with a biocompatible surfactant to minimize reaction. The compressibility of the gas enables the microbubbles to be an efficient acoustic reflector. The microbubbles are eliminated from the body via the reticuloendothelial system with their gas escaping from the lungs.
Ultrasound Imaging of Contrast Agents
Myocardial tissue is capable of reflecting an equal and opposite frequency, and this is known as a linear response . Consequently, standard two-dimensional imaging originally involved the ultrasound receiver transmitting and receiving ultrasound impulses of the same frequency, known as fundamental imaging . However, ultrasound waves become distorted on passing through the body as they encounter tissues of differing composition and density. This may change the waveform and generate frequencies different from the incident frequency. The strongest harmonic signals are multiples of the fundamental frequency. A nonlinear response is one in which harmonic frequencies of the fundamental frequency can be produced. Because microbubbles have nonlinear scattering properties, harmonic imaging was originally introduced to enhance the detection of ultrasound contrast agents within the heart. Myocardial tissue has both linear and nonlinear properties that have improved imaging of myocardial tissue using harmonic imaging, but microbubbles have greater nonlinearity and a number of techniques have been developed to help distinguish microbubbles from the surrounding tissue.
The mechanical index is a measure of the power generated by an ultrasound transducer within an acoustic field and gives an indication of the likelihood of bubble disruption. The mechanical index used during routine examinations destroys most contrast microbubbles. In order to image contrast within the LV cavity it is necessary to reduce the transmitted mechanical index, and using more contrast-specific imaging modalities this helps to remove the tissue signal and leave only the contrast. This type of imaging is very effective for LV endocardial border enhancement as it demonstrates a sharp demarcation between the contrast-enhanced cavity and the myocardium (see Fig. 11.4 ).
Administration and Indications for Use of Ultrasound Contrast Agents
Table 11.1 summarizes the characteristics of currently available ultrasound contrast agents. These ultrasound contrast agents are administered intravenously as a bolus or continuous infusion. Slow bolus injections (0.2–0.5 mL) are usually enough for the evaluation of the LV in the standard apical and parasternal views. A continuous infusion is sometimes preferred in more challenging cases to provide stable conditions for image acquisition from different views. The indications for the use of ultrasound contrast agents for LV opacification are broadly as follows:
- •
endocardial visualization and assessment of LV structure and function when two or more contiguous segments are not seen on noncontrast images;
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accurate and repeatable measurements of LV volumes and EF;
- •
to confirm or exclude apical pathology, LV thrombus, noncompaction, and ventricular pseudoaneurysm;
- •
to optimize images and diagnostic assessment of patients undergoing stress echocardiography.
| Gas | Bubble Size | Surface Coating | |
|---|---|---|---|
| Sonovue | Sulphur hexafluoride | 2–8 μm | Phospholipid |
| Optison | Perfluoropropane | 3–4.5 μm | Albumin |
| Definity | Octafluoropropane | 1.1–3.3 μm | Phospholipid |
By enhancing LV endocardial border definition, ultrasound contrast agents reduce the number of uninterpretable and technically difficult studies, increase the yield of definite apical pathology such as thrombus formation, and improve the quantification of LV volumes and EF.
Safety
Side effects have been noted with ultrasound contrast agents but these are usually mild and transient. Serious allergic reactions have been observed but are extremely rare, with an incidence of approximately 1 in 10,000 cases. Absolute contraindications for the administration of contrast agents include bidirectional or right-to-left intracardiac shunting or known hypersensitivity to the agent.
Cost-Effectiveness
By improving image quality in patients with difficult acoustic windows, the use of contrast agents may shorten the time to diagnosis, enhance decision-making, and improve workflow through the echo lab by reducing the time needed to image challenging cases. A large prospective study in patients with technically difficult echocardiographic studies showed that the use of contrast echocardiography had a positive impact on diagnosis, resource utilization, and patient management. Approximately one-third of patients had either a reduction in the number of additional diagnostic procedures, a significant alteration in medical management, or both. The impact of incorporating contrast agents was most pronounced in critically ill and hospitalized patients, those with the poorest quality images. Cost-effectiveness analysis showed a saving of $122 per patient. In the setting of stress echocardiography, contrast agents have been shown to improve visualization of regional WMAs, thereby increasing reader confidence in study interpretation and improving diagnostic accuracy. Interobserver variability of interpretation of stress echocardiograms has also been shown to improve significantly with contrast administration, particularly in less experienced hands. It has been estimated that the use of contrast agents for suboptimal images during stress echocardiography may result in a saving of $238 per patient by reducing the need for further investigation.
Myocardial Contrast Echocardiography
Ultrasound contrast agents may also be used to assess myocardial perfusion. After transit through the LV cavity, microbubbles enter the epicardial coronary arteries and the coronary microcirculation. The focus of myocardial contrast echocardiography is to use the best available imaging settings to visualize the microbubbles within the myocardium and hence assess myocardial perfusion. Continuous intravenous infusion of contrast agents is mandatory in order to provide a steady-state concentration of microbubbles and reduce the likelihood of artifacts. The technique relies on using imaging settings which initially destroy microbubbles and then observe the rate of microbubble replenishment within the myocardium.
Real-Time Imaging
High mechanical index contrast imaging leads to early destruction of microbubbles and therefore does not allow continuous real-time imaging. Real-time imaging uses a mechanical index low enough to minimize microbubble destruction and thereby strengthen the signal from microbubbles while at the same time generating little harmonic signal from myocardial tissue. Microbubbles can be intentionally destroyed by a “flash” of high mechanical index ultrasound pulses, and contrast replenishment within the myocardium may then be observed by switching to a low mechanical index setting to allow qualitative and quantitative assessment of myocardial perfusion. This method allows the benefit of real-time assessment of both wall motion and perfusion ( ).
Intermittent Imaging
After microbubble destruction with flash imaging, a high mechanical index setting may be used to assess myocardial perfusion by intermittently imaging the myocardium at end-systole after every few cardiac cycles. Intermittent imaging avoids significant microbubble destruction and thereby allows replenishment of the microbubbles into the myocardium, imaged as snapshots in end-systole when the myocardium is at its thickest and easiest to discern ( Fig. 11.5A ). The main advantage of this technique is the high sensitivity, as the harmonic signals generated by bubble destruction at a high mechanical index are stronger than those emitted at a lower mechanical index. However, continuous imaging of wall motion and perfusion is not feasible ( ).
