Contrast echocardiography: Clinical applications

INTRODUCTION — Contrast echocardiography is a technique in which use of an ultrasound-enhancing agent (UEA) improves the diagnostic performance of echocardiography [1]. The term UEA is used to describe these agents to distinguish these from radiographic iodinated contrast agents and magnetic resonance gadolinium-based contrast agents [2]. The clinical applications of contrast echocardiography will be reviewed here. Safety and optimization of the echocardiographic settings for UEAs are discussed separately. (See "Contrast echocardiography: Contrast agents, safety, and imaging technique".)

AGITATED SALINE CONTRAST — Agitated saline contrast is administered intravenously to serve as a contrast agent for the right heart and for intracardiac shunt detection.

Shunt detection — Intravenous agitated saline is well suited for detection of intracardiac or transpulmonary shunts since the air microbubbles do not cross the pulmonary circulation due to their size and short half-life. Commercially available UEAs that traverse the pulmonary vasculature (such as Definity [perflutren lipid microspheres], Lumason [sulfur hexafluoride lipid microspheres], and Optison [perflutren protein type A]) are not designed for shunt detection.

For intracardiac or pulmonary arteriovenous shunts

●Use – Agitated saline contrast is most often used to detect patent foramen ovale (PFO), atrial septal defects (ASDs), and pulmonary arteriovenous shunts.

●Technique [3]

•A commonly used method is to connect two syringes to a three-way stopcock: one syringe with 9 or 10 mL of normal saline and the other syringe with 1 mL of room air. Agitated saline solution is created by alternately flushing the contents of the two syringes into each other.

•The agitated saline solution is rapidly injected into an intravenous line connected to a 20-gauge or larger intravenous catheter (generally in a large antecubital or forearm vein).

•Echocardiographic harmonic imaging is centered on the interatrial septum with views of the right and left atria. Recording is started at least five beats prior to arrival of agitated saline contrast in the right atrium and continued for at least 10 beats after agitated saline contrast arrival in the right atrium.

•The above agitated saline injection procedure and imaging is performed at rest (with no maneuvers), as the patient coughs (at the time of arrival of agitated saline in the right atrium), and as the patient releases a Valsalva (which is achieved by asking the patient to perform that Valsalva maneuver during saline agitation and injection and then release the Valsalva when agitated saline appears in the right heart).

●Diagnostic findings – Visualization of air microbubbles in the left atrium (LA)/left ventricle (LV) after intravenous agitated saline contrast injection and right atrial opacification with microbubbles suggests the presence of an intracardiac or transpulmonary shunt [2].

•Early – The appearance of microbubbles in the LA or LV early (generally within three to five beats) after right heart opacification suggests an intracardiac shunt (ASD or PFO) [3]. However, a sinus venosus ASD may result in LA opacification simultaneous with (or before) right atrial opacification [3]. (See "Clinical manifestations and diagnosis of atrial septal defects in adults", section on 'Transthoracic echocardiogram' and "Patent foramen ovale", section on 'Ultrasound techniques'.)

•Late – Late appearance of bubbles in the LA or left heart (>5 beats) after right heart opacification suggests transpulmonic passage. Identification of only a few late bubbles may indicate clinically unimportant transpulmonic shunting. Evaluation of pulmonary arteriovenous malformations is discussed separately. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".)

●Accuracy – The sensitivity of the agitated saline contrast test using transthoracic echocardiography (TTE) is routinely enhanced by performing the test multiple times, at rest and with provocative maneuvers (eg, Valsalva and cough) [4].

The sensitivity of the test can be further enhanced, especially for detection of smaller shunts, with transesophageal echocardiography (TEE). However, some patients may have difficulty performing provocative maneuvers due to discomfort associated with the TEE probe and/or the effects of sedation for the TEE procedure. Abdominal compression maneuvers can be used in this situation.

False negatives can occur with inadequate right atrial opacification (caused by inadequate injection, brisk inferior vena cava flow, or limited transit of agitated saline to the area of the interatrial septum due to a large Eustachian valve), failure to raise right atrial pressure above LA pressure (caused by inadequate provocative maneuvers or elevated LA pressure) or failure to visualize bubbles (suboptimal acoustic windows or dislodged intravenous catheter) [3].

False positives for an intracardiac shunt (early bubbles in the LA) can occur in patients with very high output states or significant pulmonary arteriovenous shunting.

The best method to identify the location of intracardiac shunting is direct visualization of bubble passage, when possible [5].

In patients with continuous left to right flow across the ASD, a negative contrast effect (absence of agitated saline contrast) may be seen in the right atrium adjacent to the ASD [3].

●Coordination with color flow Doppler – If an ASD is clearly demonstrated by two-dimensional echocardiography with color flow Doppler, an agitated saline contrast study is not required. The diagnostic evaluation of ASD is discussed separately. (See "Clinical manifestations and diagnosis of atrial septal defects in adults", section on 'Diagnosis and evaluation'.)

Persistent left SVC — The presence of a persistent left superior vena cava (SVC) draining into the coronary sinus (or into a pulmonary vein or directly into the LA) may complicate transvenous placement of a pulmonary artery (Swan-Ganz) catheter, pacemaker, or implantable cardioverter-defibrillator lead, as well as retrograde cardioplegia [6]. This venous anomaly is usually detected incidentally.

●When to suspect left SVC – A persistent left SVC is suspected when a dilated coronary sinus is detected in the absence of a cause for elevated right atrial pressure.

●Diagnostic findings – Following injection of agitated saline contrast (or commercially available UEA) into a left arm vein, contrast appears in the coronary sinus before appearing in the right atrium [7]. 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 [6,8]. Associated venous anomalies include absence of the innominate vein and, more rarely, absence of the right SVC or drainage of the left SVC into the LA.

Other shunts — An agitated saline contrast study may also identify shunt flow in patients with ventricular septal defect (VSD) or patent ductus arteriosus (PDA) [3].

●For patients with VSDs, after agitated saline contrast opacification of the right ventricle (RV), bubbles may appear in the LV before they appear in the LA. This is most likely to occur when there is pulmonary hypertension but may also occur without pulmonary hypertension due to transient alterations in the transventricular pressure [9].

●For patients with PDA and pulmonary hypertension, after agitated saline contrast opacification of the RV, bubbles may appear in the descending aorta (before they appear in the LA) without filling of the ascending aorta [10-12].

Doppler signal enhancement — Agitated saline (or a commercially available UEA) may be used to enhance the tricuspid regurgitation continuous wave Doppler signal for estimation of RV systolic pressure. (See "Echocardiographic evaluation of the tricuspid valve", section on 'Contrast echocardiography' and "Echocardiographic assessment of the right heart", section on 'Pulmonary artery pressure'.)

COMMERCIALLY AVAILABLE UEAS — The three commercially available US Food and Drug Administration (FDA)-approved UEAs are all second-generation microsphere agents that traverse the pulmonary vasculature: Definity (Luminity in Europe; perflutren lipid microspheres), Lumason (Sonovue outside the US; sulfur hexafluoride lipid microsphere), and Optison (perflutren protein type A). Each of these agents is composed of a flexible shell containing a high molecular weight gas with low diffusivity and solubility to optimize stability [2]. These agents traverse the pulmonary and systemic capillary beds (diameter range 1.1 to 4.5 micrometers) [2].

The only FDA-approved cardiac imaging indication for UEAs is for LV blood pool opacification via an intravenous injection. There are a number of off-label cardiac imaging uses for UEAs, which are also described below.

REST ECHOCARDIOGRAPHY

Clinical use for rest echocardiography — UEA contrast rest echocardiography is recommended in the following settings, as described in the 2018 American Society of Echocardiography guideline update [2]:

●Ventricular imaging

•When two or more LV segments cannot be visualized adequately for the assessment of LV function (LV ejection fraction [LVEF] and regional wall motion [RWM]) and/or in settings in which the indication for the study requires accurate RWM analysis.

•When quantitative assessment of LVEF is important for prognosis or management of the clinical condition. Of note, biplane LV volumes obtained with UEAs are typically larger than those measured without UEAs, although the normal range for LVEF is the same.

•When RV opacification (beyond what can be achieved with agitated saline) is indicated to assess RV function, tumors, or thrombi.

•To identify or exclude post-myocardial infarction (MI) complications (including LV aneurysm, pseudoaneurysm, and thrombus) when noncontrast echocardiographic views are suboptimal.

•When the structure of LV cardiomyopathies (noncompaction cardiomyopathy or apical hypertrophy with possible aneurysm) is not adequately visualized with noncontrast echocardiography. (See "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis" and "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Apical HCM'.)

•When LV thrombus cannot be effectively identified or excluded with noncontrast echocardiography [13]. Causes of LV thrombus include MI (generally apical or posterolateral) and eosinophilic myocarditis. (See "Left ventricular thrombus after acute myocardial infarction" and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Clinical features'.)

●Atrial imaging – When TEE assessment for left atrial appendage thrombus is suboptimal or reveals significant spontaneous contrast.

●Cardiac masses – To identify and characterize cardiac masses (including use of very low mechanical index [VLMI] to assess vascularity).

●Doppler signal – As mentioned earlier, UEAs can also be used to enhance Doppler signals (see 'Doppler signal enhancement' above). Since commercial UEAs pass into the left heart, they can be used to enhance both right heart (tricuspid) or left heart (mitral or aortic) signals for evaluation of diastolic or valvular function [14].

Rationale and evidence — UEA contrast echocardiography is an accurate and timely method for evaluating LV function, is particularly helpful for patients in settings (such as an intensive care unit) in which native TTE images are frequently suboptimal, and may reduce the need for TEE or other imaging modalities in such settings [15]. Opacification of the LV cavity with a UEA enhances endocardial border detection, thus decreasing the variability in interpretation of RWM abnormalities, LV volumes, and LVEF (image 1) [2,14,16,17]. In approximately 5 to 20 percent of noncontrast echocardiographic studies, suboptimal images limit interpretation, thereby impairing the assessment of segmental and global LV systolic function [18].

Second-generation microbubble contrast agents achieve LV opacification in 90 percent of cases in which baseline images are suboptimal [19]. The success of this technique is dependent upon the intensity and homogeneity of contrast within the LV cavity. There are a variety of techniques that sonographers can use to optimize the image. (See "Contrast echocardiography: Contrast agents, safety, and imaging technique", section on 'Optimal echocardiographic settings'.)

A prospective study of 632 consecutive patients with technically difficult TTE studies evaluated the impact of contrast Definity (perflutren lipid microspheres) enhancement on diagnosis and management [20].

●With UEA contrast, 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 UEA contrast, an LV thrombus was suspected in 35 patients and definite thrombus was identified in three patients. With contrast, LV thrombus was suspected in only one patient and definite thrombus was identified in five patients.

●With UEA contrast, 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 UEA contrast increased with worsening quality of nonenhanced study, with greatest increment in quality seen in intensive care units.

STRESS ECHOCARDIOGRAPHY

Clinical use for stress echocardiography — Stress echocardiography with a UEA is recommended in the following settings when resting noncontrast echocardiography does not provide adequate visualization for regional wall motion abnormalities (RWMA) within any coronary territory. (See "Overview of stress echocardiography".)

Very low mechanical index (VLMI) imaging is the preferred imaging mode for stress echocardiography. For homogenous LV opacification, VLMI is used with intermittent flash high-mechanical index impulses (5 to 15 frames at a mechanical index of 0.8 to 1.0).

UEA dosing protocols for stress echocardiography minimize acoustic shadowing and provide steady concentrations of microbubbles via infusions of dilute UEA (for Definity and Optison), or small bolus injections (for Definity, Lumason, or Optison) with slow saline flushes.

The potential off-label use of UEAs to detect myocardial perfusion is discussed below. (See 'Future directions' below.)

Rationale and evidence — Diagnostic accuracy (sensitivity and specificity) of exercise and pharmacologic stress echocardiography requires accurate assessment of LV segmental wall motion and thickening. Improved diagnostic accuracy with UEA contrast echocardiography compared with native imaging has led many laboratories to routinely use UEA contrast with stress imaging, particularly given the general challenges of postexercise imaging [21,22].

VLMI techniques enhance detection of RWMA and subendocardial wall thickening abnormalities.

The efficacy of UEA contrast echocardiography for the assessment of LV wall motion abnormalities was evaluated in a retrospective multicenter study of 4011 patients with suboptimal native echocardiographic images who underwent dobutamine stress echocardiography with UEA for evaluation of suspected coronary artery disease (CAD) [23]. Sensitivity and diagnostic accuracy for detection of significant CAD (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 a UEA contrast agent. Sensitivity and diagnostic accuracy were similar in the group with initially suboptimal images receiving UEA compared with those with optimal images without UEA (81 versus 73 percent and 82 versus 77 percent).

ALCOHOL SEPTAL ABLATION — The off-label use of UEA to guide alcohol septal ablation as a treatment for outflow obstruction in patients with hypertrophic cardiomyopathy is discussed separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction", section on 'Septal reduction therapy'.)

FUTURE DIRECTIONS — Myocardial contrast echocardiography (MCE) is not an FDA-approved indication and clinical experience is limited. Studies of MCE have investigated its utility for detection of CAD and assessment of prognosis.

When myocardial perfusion imaging with a UEA is combined with contrast assessment of wall motion abnormalities, the technique is referred to as real-time myocardial contrast echocardiography (RTMCE). Studies comparing RTMCE with standard contrast stress echocardiography (assessing wall motion only) have found that RTMCE may improve the accuracy of detection of obstructive CAD [24-26] and may also have prognostic value [24,25].

●In a prospective randomized comparison of RTMCE and standard contrast stress echocardiography among 2063 patients referred for stress echocardiography for suspected CAD, RTMCE identified more resting wall motion abnormalities (13 versus 9 percent) as well as significantly more abnormal stress tests (30 versus 22 percent) [25]. An abnormal RTMCE more frequently resulted in revascularization than an abnormal standard contrast stress echocardiogram. Resting wall motion abnormalities seen with RTMCE were an independent predictor of death/nonfatal MI but resting wall motion abnormalities identified by standard contrast stress echocardiography were not.

●In a retrospective study of 788 patients who underwent dobutamine stress echocardiography with UEA contrast for RTMCE, 75 patients (9.6 percent) died or had a nonfatal MI at follow-up [24]. Abnormal myocardial perfusion added significant incremental predictive value to clinical factors, 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.

Studies have found that RTMCE (or myocardial perfusion imaging with UEA) correlates with regional tracer uptake in nuclear single photon emission computed tomography (SPECT) imaging for detection of CAD [27-29]. The largest multicenter study included 516 patients, each of whom underwent radiographic coronary angiography, dipyridamole stress SPECT examination, and RTMCE using Lumason [29]. Both SPECT and RTMCE were blindly interpreted by three separate experts, while coronary angiograms were assessed quantitatively. There was only fair agreement among the three experts. Thirty-one percent of patients had >70 percent stenosis. RTMCE 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 MI, proximal disease, 50 percent stenosis).

SUMMARY AND RECOMMENDATIONS

●Definition – Contrast echocardiography is a technique that uses ultrasound-enhancing agents (UEAs) to improve the diagnostic performance of echocardiographic studies. (See 'Introduction' above.)

●Agitated saline contrast – Agitated saline contrast is used to identify intracardiac shunts (particularly patent foramen ovale [PFO] and atrial septal defects [ASDs]), pulmonary arteriovenous shunts, and persistent left superior vena cava (SVC). It is also used to enhance tricuspid regurgitation continuous wave Doppler spectra for estimation of right ventricular (RV) systolic pressure. Agitated saline may be beneficial for both transthoracic echocardiographic (TTE) and transesophageal echocardiographic (TEE) studies. (See 'Agitated saline contrast' above.)

●Commercially available UEAs – The commercially available UEAs are second-generation microsphere agents that traverse the pulmonary vasculature. The only US Food and Drug Administration (FDA)-approved cardiac imaging indication for these UEAs is for left ventricular (LV) blood pool opacification via intravenous injection. (See 'Commercially available UEAs' above.)

•Rest transthoracic echocardiography – For rest TTE, commercially available UEAs are used to assess global and segmental left and right ventricular wall motion, to identify LV structural abnormalities (such as noncompaction cardiomyopathy, aneurysm, or pseudoaneurysm), to identify intracardiac thrombus/masses, and to enhance Doppler signals. (See 'Rest echocardiography' above.)

•Stress echocardiography – For stress echocardiography, commercially available UEAs are used to assess global and segmental LV wall motion at rest and with stress. Real-time myocardial contrast echocardiography (RTMCE) is an off-label use of UEA to detect myocardial perfusion, which may aid in the detection of myocardial ischemia and viability. (See 'Stress echocardiography' above.)

●Alcohol septal ablation – The off-label use of UEA to guide alcohol septal ablation as a treatment for outflow obstruction in patients with hypertrophic cardiomyopathy is discussed separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction", section on 'Septal reduction therapy'.)

●Myocardial contrast echocardiography – Myocardial contrast echocardiography (MCE) is not an FDA-approved use of UEAs, and clinical experience is limited. Studies of MCE have investigated its utility for detection of coronary artery disease (CAD) and assessment of prognosis. (See 'Future directions' above.)