INTRODUCTION — Contrast echocardiography is a technique for improving echocardiographic endocardial border delineation and providing real time assessment of intracardiac blood flow. Agitated saline contrast provides contrast in the right heart and enables detection of right-to-left shunts. Opacification of the left ventricular (LV) cavity by contrast agents developed to traverse the pulmonary vasculature permits improved left ventricular endocardial border detection, thus improving the assessment of left ventricular dimensions and wall motion. Contrast echocardiography can also enhance delineation of Doppler signal. Additional uses of contrast echocardiography include assessment of myocardial perfusion.
In a 2018 update of the American Society of Echocardiography (ASE) Guidelines, an alternative name for echocardiographic contrast agents as ultrasound-enhancing agents (UEAs) was proposed to help patients and providers distinguish these agents from other iodinated contrast agents and gadolinium [1]. The only currently US Food and Drug Administration-approved indication for the use of UEAs in cardiac imaging is for left ventricular opacification via an intravenous injection. There are many other off-label uses for UEAs.
The current and potential clinical applications of this technique will be reviewed here. The development and safety of microbubbles for echocardiographic contrast and the optimization of the echocardiographic settings for visualizing contrast are discussed separately. (See "Contrast echocardiography: Contrast agents, safety, and imaging technique".)
CLINICAL APPLICATIONS FOR AGITATED SALINE CONTRAST
Shunt detection — The first clinical use of contrast echocardiography was for detection of right-to-left shunts [2]. Agitated saline given intravenously is well suited for this purpose because microbubbles of air formed from agitating saline persist long enough to opacify the right heart chambers and diffuse into the lungs when traveling through the pulmonary circulation. Therefore, microbubbles will not gain access to the left heart chambers unless a right-to-left intracardiac or extracardiac shunt is present.
This technique is used most often for the detection of patent foramen ovale and atrial septal defects, although it can also be used to detect ventricular septal defects and arteriovenous shunts in the pulmonary vasculature. The appearance of bubbles in the left heart early (within three to five beats) after right chamber opacification suggests an intracardiac shunt [3]. Later appearance of bubbles in the left heart (>5 beats after first seeing bubbles in the right atrium) suggests pulmonary arteriovenous shunting. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults" and "Clinical manifestations and diagnosis of atrial septal defects in adults".)
The sensitivity is enhanced with multiple injections, as well as with provocative maneuvers such as Valsalva and coughing [4]. However, it is important to note that this is a general guide. False negatives can occur with inadequate injection, inadequate provocative maneuvers, and inability to increase right atrial pressure greater than left atrial pressure. False positives can also occur in patients with very high-output states and significant pulmonary arteriovenous shunting. The best method to predict the location of the shunting is direct visualization of bubble passage, which may not always be possible [5].
Microbubble contrast agents such as Optison (perflutren protein type A), Definity (perflutren lipid microspheres), and Lumason (sulfur hexafluoride lipid microsphere) that traverse the pulmonary vasculature are NOT designed for shunt detection.
Doppler signal enhancement — Agitated saline (and other ultrasound contrast agents) may be used to enhance tricuspid Doppler signals for use in assessment of transvalvular velocity to estimate right ventricular systolic pressure. (See "Echocardiographic evaluation of the tricuspid valve", section on 'Contrast echocardiography'.)
Diagnosis of persistent left superior vena cava — Agitated saline (or other ultrasound) contrast can help confirm the diagnosis of persistent left superior vena cava (SVC). This venous anomaly is usually detected incidentally. A persistent left SVC is suspected when a dilated coronary sinus is detected in the absence of a cause for elevated right atrial pressure. A persistent left superior vena cava drains directly into the coronary sinus leading to a characteristic sequence of contrast appearance: following injection of contrast into a left arm vein, contrast appears in the coronary sinus before appearing in the right atrium [6]. Upon intravenous injection of contrast into the right arm, there is normal transit of contrast with right atrial opacification before appearance of contrast in the coronary sinus.
Associated cardiovascular anomalies are present in a minority of patients with persistent left SVC [7,8]. Associated venous anomalies include absence of the innominate vein and more rarely absence of the right superior vena cava or drainage of the left SVC into the left atrium.
The presence of a left SVC may complicate transvenous placement of pulmonary artery (Swan-Ganz) catheters, pacemaker or implantable cardioverter-defibrillator leads, as well as retrograde cardioplegia [8].
CLINICAL APPLICATIONS FOR MICROBUBBLE CONTRAST AGENTS
Endocardial border definition — The second generation microbubble contrast agents (Definity (perflutren lipid microspheres), Optison (perflutren protein type A), and Lumason (Sulfur hexafluoride lipid microsphere), which are available in most countries) traverse the pulmonary vasculature and are indicated for LV opacification and LV endocardial border definition in patients with technically suboptimal echocardiograms [9-12]. In the 2011 ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR Appropriate Use Criteria for Echocardiography, the use of contrast is considered appropriate when >2 contiguous LV segments are not seen on noncontrast images [13]. (See "Contrast echocardiography: Contrast agents, safety, and imaging technique".)
Rest echocardiography — Suboptimal images limit the interpretation in approximately 5 to 20 percent of echocardiographic studies, thereby impairing the assessment of segmental and global LV systolic function [10]. Contrast opacification of the LV cavity enhances border detection, decreasing the variability in the interpretation of regional wall motion abnormalities, LV volumes and remodeling, and the ejection fraction (EF) (image 1) [14-18]. It is an accurate and cost-effective method for evaluating LV function in situations where obtaining a study is technically difficult, such as in the intensive care unit [19].
The success of this technique is dependent upon the intensity and homogeneity of contrast within the LV cavity. There is a variety of techniques that sonographers can use to optimize the image [20]. Second-generation microbubble contrast agents achieve LV opacification in 90 percent of cases in which baseline images are suboptimal [15].
A prospective study of 632 consecutive patients with technically difficult echocardiographic studies evaluated the impact of contrast Definity (perflutren lipid microspheres) enhancement on diagnosis and management [21].
●With contrast enhancement, the percent of uninterpretable studies decreased from 11.7 to 0.3 percent and technically difficult studies decreased from 86.7 to 9.8 percent.
●Without contrast, an LV thrombus was suspected in 35 patients and definite thrombus was identified in three patients. With contrast enhancement, LV thrombus was suspected in only one patient and definite thrombus was identified in five patients.
●With contrast enhancement, additional procedures were avoided in 32.8 percent of patients and drug management was altered in 10.4 percent, with some change in management in a total of 35.6 percent of patients.
●The impact of contrast increased with worsening quality of nonenhanced study, with greatest increment in quality seen in intensive care units.
The following clinical applications were suggested in the 2008 American Society of Echocardiography (ASE) guidelines [14]:
●Difficult to image patients presenting for rest echocardiography with reduced image quality:
•To enable improved endocardial visualization and assessment of LV structure and function when ≥2 contiguous segments are not seen on noncontrast images.
•To reduce variability and increase accuracy in LV volume and LVEF measurements by two-dimensional (2D) echocardiography.
•To increase the confidence of the interpreting clinician in LV functional, structure, and volume assessments.
●In all patients presenting for rest echocardiographic assessment of LV systolic function (not solely difficult-to-image patients):
•To reduce variability in LV volume measurements through 2D echocardiography.
•To increase the confidence of the interpreting clinician in LV volume measurement.
●To confirm or exclude the echocardiographic diagnosis of the following LV structural abnormalities, when nonenhanced images are suboptimal for definitive diagnosis:
•Apical variant of hypertrophic cardiomyopathy.
•LV noncompaction.
•Apical thrombus.
•Complications of myocardial infarction, such as LV aneurysm, pseudoaneurysm, and myocardial rupture.
●To assist in the detection and correct classification of intracardiac masses, including tumors and thrombi.
●For imaging in the intensive care unit (ICU) when standard tissue harmonic imaging does not provide adequate cardiac structural definition.
Stress echocardiography — Diagnostic exercise and pharmacologic stress echocardiography depend upon the accurate assessment of segmental wall motion and thickening. Improved sensitivity with contrast echocardiography, as compared with conventional stress imaging, has led many laboratories to routinely use contrast during stress imaging [22,23].
Echocardiographic contrast administration during stress echocardiography is commonly performed to better define endocardial borders in patients with suboptimal echocardiographic images (to enhance the detection of wall motion abnormalities). Additionally, the administration of echocardiographic contrast can be performed for the concurrent assessment of myocardial perfusion. When perfusion imaging is combined with contrast assessment of wall motion abnormalities, the process is typically referred to as real-time myocardial contrast echocardiography (RTMCE).
The efficacy of contrast echocardiography for the assessment of wall motion abnormalities was evaluated in a retrospective multicenter study of 4011 patients undergoing dobutamine stress echocardiography for evaluation of suspected coronary heart disease (CHD) [24]. All patients received Definity (perflutren lipid microspheres) or Optison (perflutren protein type A) for rest and peak stress imaging. Sensitivity and diagnostic accuracy for detection of significant CHD (defined as >50 percent coronary artery stenosis by quantitative angiography) was compared with that obtained in 1923 matched patients with optimal images on stress echocardiography without use of contrast. Sensitivity and diagnostic accuracy were slightly but not significantly higher in the group receiving contrast (81 versus 73 percent and 82 versus 77 percent).
RTMCE has been studied in a number of prospective cohorts, in comparison with both standard contrast stress echocardiography (assessing wall motion only) and myocardial perfusion imaging, and has generally been as good or better than other imaging techniques for the diagnosis of obstructive CHD [25-27]. As an example, in a prospective randomized comparison of RTMCE and standard contrast stress echocardiography among 2063 patients (mean age 59 years, 53 percent female) referred for stress echocardiography for suspected CHD, RTMCE identified more resting wall motion abnormalities (13 versus 9 percent) as well as significantly more abnormal stress tests (30 versus 22 percent) [25]. RTMCE improved the detection of CHD compared with standard contrast stress echocardiography.
Preliminary data suggest that stress echocardiography may provide an advantage over radionuclide myocardial perfusion imaging (rMPI) in women by overcoming the problem of nuclear image attenuation [28]. Small studies found that dobutamine stress echocardiography had similar sensitivity and similar or greater specificity as compared with rMPI [29-31]. Contrast LV opacification may further improve diagnostic accuracy, although this has not been directly compared with rMPI in women. (See "Artifacts in SPECT radionuclide myocardial perfusion imaging".)
The 2008 ASE guidelines suggest contrast echocardiography for difficult-to-image patients presenting for stress echocardiography with suboptimal image quality [14]:
●To obtain diagnostic assessment of segmental wall motion and thickening at rest and stress
●To increase the proportion of diagnostic studies
●To increase reader confidence in interpretation
Enhancement of Doppler signal — These agents, like agitated saline, can be used to enhance Doppler signals. Since these agents pass into the left heart, they can be used to enhance right heart (tricuspid) or left heart (mitral or aortic) signals for evaluation of diastolic or valvular function [14].
ADDITIONAL APPLICATIONS
Alcohol septal ablation — Contrast echocardiography can be used to guide alcohol septal ablation used as a treatment to diminish LV outflow obstruction in patients with hypertrophic cardiomyopathy. Injection of one of the second-generation echocardiographic contrast agents into the proposed target septal arteries to determine the territory supplied by them is key to the success of the procedure, as defined by at least a 50 percent reduction in left ventricular outflow tract (LVOT) gradient [32]. After the target septal perforator is identified, a balloon catheter is advanced into the vessel and inflated. One to 2 mL of a diluted echocardiographic contrast agent is injected through the balloon catheter during continuous echocardiographic imaging. A well-demarcated area with increased echodensity in the basal septum will be noted on echocardiographic imaging. It is important to ensure the absence of perfusion of other myocardial segments away from the targeted areas [32]. If other areas are noted to be involved, this may lead to a change in the target vessel [33]. Myocardial contrast echocardiography (MCE) can accurately delineate the size of the septal vascular territory prior to ethanol injection and can predict the infarct size that results from ethanol infusion [34]. (See "Hypertrophic cardiomyopathy: Nonpharmacologic treatment of left ventricular outflow tract obstruction".)
The 2011 ASE clinical recommendations for multimodality cardiovascular imaging of patients with hypertrophic cardiomyopathy endorse the use of MCE during alcohol septal ablation, and list the following advantages: shorter intervention time, shorter fluoroscopy time, fewer occluded vessels, smaller amount of ethanol used, smaller infarct size, lower likelihood of heart block, and higher likelihood of success [32]. The use of agitated radiographic contrast for this purpose was also described in the 2008 ASE consensus statement on ultrasound contrast agents [14]. Consensus guidelines from the European Society of Cardiology in 2014 and the American College of Cardiology/American Heart Association in 2020 also endorse this practice [35,36]. However, US Food and Drug Administration (FDA)-approved labeling for Optison, Definity (perflutren lipid microspheres), and Lumason (sulfur hexafluoride lipid microsphere) notes that intraarterial injection is contraindicated.
Myocardial perfusion — Portable real-time, noninvasive assessment of myocardial perfusion may become possible with improved contrast echocardiography agents and detection algorithms. Since microbubble size is consistently smaller than erythrocyte size (10 microns), contrast reliably transverses the microvasculature.
Controlled investigations with newer, second generation agents have shown that routine intravenous injection accurately identifies myocardial perfusion [37,38]. Among patients with coronary artery disease, studies have found a variable correlation between contrast echocardiography and regional tracer uptake in nuclear single photon emission computed tomography (SPECT) imaging, which were probably due to the need for continued improvement and refinement of acquisition techniques with perfusion imaging and inexperience of the investigators [39,40]. The largest multicenter study included 516 patients, each of whom underwent coronary angiography, SPECT examination, and MCE using SonoVue. Both SPECT and MCE were blindly interpreted by three separate experts, while angiograms were assessed quantitatively. Thirty-one percent of patients had >70 percent stenosis. MCE yielded superior sensitivity (75 versus 49 percent) to SPECT but inferior specificity (52 versus 81 percent, respectively). Similar results were obtained in subgroup analyses (single versus multivessel disease, prior myocardial infarction, proximal disease, 50 percent stenosis). The three experts showed only a fair degree of agreement [41]. In some studies, real-time MCE obtained during exercise or vasodilator correlated well with SPECT imaging, including localization of the vascular territory involved [42,43].
Other possible settings in which information concerning the extent of coronary artery disease derived from contrast echocardiography may be clinically useful include the following:
●Because symptoms and electrocardiographic changes do not always accurately identify ischemia in patients with chest pain in the emergency department, perfusion information obtained via nuclear cardiology has been utilized to help identify low risk patients [44] (see "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department"). Contrast echocardiography may provide similar myocardial perfusion information without the difficulties of transporting the patient to a nuclear scanner. In addition, echocardiography provides wall motion information that further identifies chest pain patients at high risk for ischemia. (See "Role of echocardiography in acute myocardial infarction".)
Contrast echocardiography also may enhance the predictive value of standard dobutamine echocardiography. The potential value of this approach was illustrated in a retrospective study of 788 patients who underwent dobutamine stress with injection of microbubbles for real-time contrast echocardiography; 75 patients (9.6 percent) died or had a nonfatal MI at follow-up [45]. Abnormal myocardial perfusion added significant incremental predictive value to clinical factors, the resting LVEF, and wall motion abnormalities. The three-year event-free survival was 95 percent in patients with normal wall motion and myocardial perfusion, 82 percent with normal wall motion and abnormal myocardial perfusion, and 68 percent for abnormalities in both wall motion and myocardial perfusion. Three-year event-free survival varied with multivessel perfusion defects (56 versus 85 percent with a single vessel perfusion defect).
Hence, there is a growing body of evidence suggesting the utility of contrast echocardiography to evaluate myocardial perfusion. However, there is no contrast agent yet FDA approved for that purpose.
Myocardial viability — Myocardial viability assessment, particularly in the high risk patient with LV dysfunction, has had increasing importance in patient management and decision making. Current techniques used to determine myocardial viability include SPECT imaging, positron emission tomography scanning, nuclear magnetic imaging, and low-dose dobutamine echocardiography. (See "Evaluation of hibernating myocardium" and "Dobutamine stress echocardiography in the evaluation of hibernating myocardium" and "Assessment of myocardial viability by nuclear imaging in coronary heart disease".)
By providing simultaneous LV function and perfusion information via a single modality, contrast echocardiography offers the advantages of improved image resolution (over SPECT), portability, cost economy, and practicality. The threshold of flow detectable with contrast echocardiography is comparable to the level of flow necessary to maintain viability (15 percent of normal or 0.25 mL/min per kg), thereby providing a rationale for contrast echocardiography as a potential tool to identify viable myocardium [46]. The identification of subnormal flow (heterogeneous contrast effect) as opposed to no flow (fixed contrast defect) or normal flow (homogeneous contrast) within dysfunctional myocardium may predict long-term recovery of function following the restoration of normal blood supply [47].
Stunned myocardium — Dysfunctional segments of the LV following an ischemic insult may represent either infarcted or stunned tissue. Contrast echocardiography may be helpful in differentiating these two patterns of myocardial dysfunction. Stunned myocardium has homogeneous myocardial contrast, representing normal blood flow with an intact microvasculature. Such a pattern implies either that the decrease in perfusion was not lethal or that reperfusion (either spontaneous or as a result of intervention) occurred prior to necrosis. In this setting, systolic function is likely to return over the next several weeks [48-51]. In one study of 96 patients with recent myocardial infarction, the positive and negative predictive value of homogeneous opacification for recovery of contractile function at six months was 47 and 84 percent, respectively; the positive predictive value for predicting functional recovery was 78 percent in those who were revascularized [50]. (See "Clinical syndromes of stunned or hibernating myocardium".)
In the absence of complete reperfusion, the identification of heterogeneous contrast effect within dysfunctional segments may represent collateral or partial anterograde blood supply within an area at risk; this also provides important prognostic information by predicting a more limited infarct [52,53].
Hibernating myocardium — Hibernation is the metabolic adaptation and downregulation that occurs following a chronic ischemic insult. As with stunned myocardium, necrotic transformation is avoided and microvascular integrity is maintained, but blood flow and systolic function remain suboptimal. In this setting, findings obtained via contrast echocardiography may be informative. As an example, when myocardial contrast (which was representative of collateral flow) was present in one study, myocardial dysfunction within an infarct zone improved to a greater degree following revascularization than when collateral flow could not be demonstrated [53]. The degree of contrast homogeneity may be proportional to the extent of functional recovery [54,55]. (See "Pathophysiology of stunned or hibernating myocardium".)
In the detection of hibernating myocardium, contrast echocardiography compares well to both dobutamine echocardiography and thallium scintigraphy [56-61]. In one study, 20 patients with coronary disease and ventricular dysfunction underwent MCE, dobutamine echocardiography, and rest-redistribution thallium scintigraphy prior to coronary artery bypass grafting (CABG) [60]. Echocardiography was repeated three to four months after surgery. The sensitivity of MCE in detecting segments with recovery of function after surgery was comparable to that of dobutamine echocardiography or thallium scintigraphy (90, 80, and 92 percent, respectively), and the specificity was significantly greater (63, 54, and 45 percent, respectively). (See "Evaluation of hibernating myocardium".)
Intraventricular flow patterns — In addition to improving endocardial border detection by LV opacification, the intraventricular dynamics of contrast exhibits characteristic flow patterns during the cardiac cycle, which may be associated with LV segmental or global function. One study of 348 patients found two different patterns of intracavitary contrast flow, as visualized in apical views [62]:
●A swift, vertical, and homogeneous flow towards the apex; 91 percent of patients with this pattern had normal LV segmental function and 93 percent had normal global LV function (image 2).
●A distinctly protracted, swirling, and heterogeneous pattern; 99 percent of patients with this pattern had one or more wall motion abnormality and 83 percent had various degrees of LV dysfunction (image 3).
SUMMARY AND RECOMMENDATIONS
●Contrast echocardiography is a technique for improving echocardiographic border delineation that can also enhance delineation of Doppler signal, permit detection of right-to-left shunts, and assess myocardial perfusion. (See 'Introduction' above.)
●Agitated saline contrast is most commonly used for the detection of right-to-left shunts, although it can also be useful for enhancing Doppler signal and detecting a persistent left superior vena cava. (See 'Clinical applications for agitated saline contrast' above.)
●Microbubble contrast opacification of the left ventricular (LV) cavity enhances endocardial border detection, decreasing the variability in the interpretation of regional wall motion abnormalities, LV volumes and remodeling, and the ejection fraction (EF) (image 1). Microbubble contrast can be used to enhance both resting and stress echocardiography as well as Doppler imaging. (See 'Clinical applications for microbubble contrast agents' above.)
●The only currently US Food and Drug Administration-approved indication for the use of ultrasound-enhancing agents (UEAs) in cardiac imaging is for LV opacification via an intravenous injection. There are other off-label uses of UEAs. (See 'Additional applications' above.)
