I

Introduction

The use of ultrasound enhancing agents (UEAs) has become an integral component of echocardiography practice. Since the 2008 American Society of Echocardiography (ASE) consensus statement on clinical applications of ultrasound contrast agents, there have been several important developments that require the document be revised into a guidelines paper.

• 1.
  

  The term ultrasound contrast agents , describing a class of products comprising microbubbles to enhance ultrasound signals, was replaced with the less conflicting term ultrasound enhancing agent. Although the Writing Group understands the need for this terminology in helping patients and referring physicians distinguish these substances from iodinated contrast agents or gadolinium chelates, it was considered equally acceptable to refer to these agents as contrast agents and the imaging techniques as contrast echocardiography or myocardial contrast echocardiography (MCE).

  
  
• 2.
  

  The Intersocietal Accreditation Commission has required that policies be in place for UEA use (section 1.6.2.4B , updated June 1, 2017) in specific clinical settings in which UEAs are required.

  
  
• 3.
  

  The safety of UEAs has been documented in several different clinical scenarios (stress echocardiography, pulmonary hypertension, intracardiac shunting) as well as in emergency department (ED), critical care, and pediatric settings. Propensity-matched studies have not only documented safety but also demonstrated the potential value and importance of early UEA use in improving patient outcomes ( Table 1 ). These large single- and multicenter studies have led to changes in the US Food and Drug Administration (FDA) boxed warnings regarding UEA use in pulmonary hypertension, critical care settings, and more recently, known or suspected right-to-left shunts.

  
  
  
  

  Table 1

  
  

  Large studies (>1,000 patients) published since 2008 that evaluated UEA safety

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Study	Design	UEA	Total patients	UEA patients	Control patients	Inpatient/outpatient	Rest/stress	Outcomes
  Aggeli et al. (2008)	Prospective	Sonovue	5,250	5,250	NA	NR	Stress	No deaths or myocardial infarctions
  Gabriel et al. (2008)	Retrospective	Definity or Optison ∗	9,798	4,786	5,012	95% Outpatients	Stress	No increased rate of SAEs or mortality at 24 h in UEA patients
  Herzog et al. (2008)	Retrospective	Definity or Optison	16,025	16,025	NA	Both	Both	No short-term mortality; SAEs in 0.031%
  Kusnetzky et al. (2008)	Retrospective	Definity	18,671	6,196	12,475	Inpatients	Rest	No increased mortality in UEA patients
  Main et al. (2008)	Retrospective	Definity	4,300,966	58,254	4,242,712	Inpatients	Rest	No increased mortality in UEA patients
  Shaikh et al. (2008)	Retrospective	Definity or Optison	5,069	2,914	2,155	Both	Stress	No increased risk for SAEs in UEA patients
  Wei et al. (2008)	Retrospective	Definity or Optison	78,383	78,383	NA	Both	Both	Severe allergic reactions in 0.01% and anaphylactoid reactions in 0.006%
  Abdelmoneim et al. (2009)	Retrospective	Definity or Optison	26,774	10,792	15,982	Both	Stress	No increased short- or long-term mortality in UEA patients
  Anantharam et al. (2009)	Retrospective	Definity or Lumason †	3,704	1,150	2,554	Both	Stress	No increased SAEs in UEA patients
  Dolan et al. (2009)	Retrospective	Definity or Optison	66,220	42,408	23,812	NR	Both	No increased mortality in UEA patients
  Abdelmoneim et al. (2010)	Retrospective	Definity or Optison	16,434	6,164	10,270	Both	Stress	No increased risk for myocardial infarction or mortality in UEA patients with pulmonary hypertension
  Exuzides et al. (2010)	Retrospective	Optison	14,500	2,900	11,600	Inpatients	Rest	No increased mortality in UEA patients
  Goldberg et al. (2012)	Retrospective	Definity	96,705	2,518	94,187	Both	Both	No increased mortality in UEA patients
  Weiss et al. (2012)	Prospective	Definity	1,053	1,053	NA	NR	Both	No deaths or SAEs
  Wever-Pinzon et al. (2012)	Retrospective	Definity	1,513	1,513	NA	Inpatients	Both	No deaths or SAE attributed to UEA in pulmonary hypertension patients
  Platts et al. (2013)	Retrospective	Definity	5,956	5,956	NA	Both	Both	No increased mortality in UEA patients
  Main et al. (2014)	Retrospective	Definity	32,434	16,217	16,217	Inpatients	Rest	Lower mortality in UEA patients
  Wei et al. (2014)	Prospective	Optison	1,039	1,039	NA	Outpatients	Both	No deaths or SAEs

   
  

  NA , Not applicable; NR , not reported; SAE , serious adverse event.

  
  

  Modified with permission from Muskula et al.

  
  

  ∗ Definity is marketed as Luminity in Europe.

  
  

  † Lumason is marketed as SonoVue in Europe.

  
  
  
  
• 4.
  

  Numerous clinical trials have demonstrated the safety and efficacy of UEAs in new stress echocardiography settings (dipyridamole, adenosine, regadenoson, bicycle, and treadmill), as well as in different resting conditions in which regional wall motion (RWM) and perfusion information provide significant incremental value in predicting patient outcomes ( Table 2 ).

  
  
  
  

  Table 2

  
  

  Smaller studies (<1,000 patients) published since 2009 that evaluated UEA safety

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Study	Design	UEA	Total patients	UEA patients	Control patients	Inpatient/outpatient	Modality	Outcomes
  Kurt et al. (2009)	Prospective	Definity	632	632	NA	545 inpatient, 87 outpatient	Rest	1 serious AE, 5 minor AEs (back pain) ∗
  Senior et al. (2013)	Prospective	Sonovue	630	628	NA		Stress	1 serious AE, 16 minor AEs, 2.5% (nausea, headache) †
  Main et al. (2013)	Prospective	Optison	33	30	NA	Outpatient	Rest (PASP > 35 mm Hg)	No serious AEs
  Wei et al. (2012)	Prospective	Definity	32	32	16 with PASP < 35 mm Hg	Outpatient	Rest (16 with PASP > 35 mm Hg)	No serious AEs, 1 mild AE (back pain, headache)
  Kutty et al. (2016)	Retrospective	Definity	113	113	140	Outpatient	Rest and stress	13 minor AEs (<1 min in duration, no treatment)
  Fine et al. (2014)	Retrospective	Definity, Optison	251	10	NA	Inpatient	LVAD patients	No complications related to UEA, no AEs, no change in device parameters
  Bennett et al. (2016)	Retrospective	Perflutren, Definity, Optison	1,996	4	NA	Inpatient	ECMO patients	No complications related to UEA, no AEs, no change in device parameters
  Kalra et al. (2014)	Retrospective	Definity, Optison	39,020 UEA patients	418 with right-to-left shunts ‡	NA	NA	Rest	No primary AEs, 1 minor AE (back pain) in the shunt group

   
  

  AE , Adverse event; ECMO , extracorporeal membrane oxygenation; LVAD , LV assist device.

  
  

  ∗ Death after 5 hours of UEA administration; patient experienced a large anterior wall myocardial infarction after knee replacement with hypotension, recurrent ventricular tachycardia within the 24 hours before echocardiography.

  
  

  † A 69-year-old woman with suspected myocarditis developed hypersensitivity-like symptoms and asystole for 30 sec (symptom-free recovery within 57 min).

  
  

  ‡ Left-to-right shunts excluded.

  
  
  
  
• 5.
  

  The use of myocardial perfusion (MP) imaging with UEAs has increased, specifically in the setting of stress echocardiography, chest pain evaluation in the ED, and in the evaluation of intracardiac masses. The American Medical Association Current Procedural Terminology (CPT) Panel approved a category III (“emerging technology”) CPT code (+0439T) for “myocardial contrast perfusion echocardiography; at rest or with stress, for assessment of myocardial ischemia or viability” (effective July 1, 2016) for the use of perfusion imaging as an add-on to the following base CPT codes: 93306, 93307, 93308, 93350, and 93351. Although this category III code is not reimbursed by the Centers for Medicare and Medicaid Services in the United States, approval of this code acknowledges the significant incremental value of MP with UEAs in several clinical settings.

  
  
• 6.
  

  A critical mass of data have been published that demonstrates the beneficial effect of UEAs on early outcomes in critically ill patients and the cost-effectiveness of UEAs in patients with suboptimal windows in a wide variety of clinical settings.

  
  
• 7.
  

  The FDA in the United States has approved new UEAs ( Table 3 ). New agents have been approved in other North American and South American countries. Ultrasound manufacturers have also revised their left ventricular opacification (LVO) and low–mechanical index (MI) settings for optimal enhancement. Specific instrumentation guidelines are now provided to optimize left ventricular (LV) RWM and perfusion analysis ( Table 4 ).

  
  
  
  

  Table 3

  
  

  The three commercially available UEAs

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Name	Manufacturer/vial contents	Mean diameter	Shell	Gas	Contraindications
  Lumason (sulfur hexafluoride lipid-type A microspheres)	Bracco Diagnostics, 5 mL	1.5–2.5 μm (maximum 20 μm, 99% ≤10 μm)	Phospholipid	Sulfur Hexafluoride	Allergy to sulfur hexafluoride
  Definity (perflutren lipid microsphere)	Lantheus Medical Imaging, 1.5 mL	1.1–3.3 μm (maximum 20 μm, 98% <10 μm)	Phospholipid	Perflutren	Allergy to perflutren
  Optison (perflutren protein type-A microspheres)	GE Healthcare, 3.0 mL	3.0–4.5 μm (maximum 32 μm, 95% <10 μm)	Human albumin	Perflutren	Allergy to perflutren/blood products

   
  
  
  
  

  Table 4

  
  

  Location and description of VLMI imaging software on commercially available echocardiographic scanners

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Manufacturer	Platform and portability ∗	Location and name of enhanced imaging software on front end	High-MI “flash” impulse location on front end	Specific pulse sequence scheme used (dominant nonlinear activity detected)	Frequency/MI recommended for VLMI imaging
  Philips	iE33 Not portable	Contrast key On/off LVO and low-MI choices	Touch screen/flash label	Amplitude modulation and pulse inversion (fundamental and harmonic)	<2.0 MHz/MI < 0.2 (GEN or PEN setting)
  Philips	Epiq Not portable	Contrast key On/off Low-MI and LVO choices	Touch screen/flash label	Amplitude modulation and pulse inversion (fundamental and harmonic)	<2.0 MHz/MI < 0.2 (GEN or PEN setting)
  Philips	CX50 Portable	Contrast key On/off LVO choice	Control panel	Amplitude modulation (harmonic)	<2.0 MHz/MI < 0.3
  GE	Vivid E95 Not portable	Advanced contrast option	Touch screen/ flash label	Pulse inversion 1.5/3.0 and 1.6/3.2 MHz and 1.7/3.4 MHz (harmonic) Amplitude modulation 2.1 and 2.4 MHz (fundamental and harmonic)	1.5–1.7 MHz/MI < 0.2 2.1–2.4 MHz/MI < 0.2
  Siemens	SC2000 Not portable		Not available; need to use “color Doppler” knob	Pulse inversion and alternating polarity/amplitude (fundamental and harmonic)	2.0 MHz/MI < 0.2
  Toshiba	Aplio i900 Not portable	Touch screen/CHI label	Control panel	Pulse subtraction (amplitude modulation; harmonic)	h3.5/MI < 0.2 (PEN setting)
  Toshiba	Aplio 500 Not portable	Touch screen/low label	Touch screen/flash label	Pulse subtraction (amplitude modulation; harmonic)	h2.8–h3.6/MI < 0.2
  Esaote	MyLabEight Not portable	Contrast key On/off LVO choice	Touch screen/flash label	Phase cancellation	PEN frequency/MI < 0.2
  Esaote	MyLabSeven Not portable	Contrast key On/off LVO choice	Touch screen/flash label	Phase cancellation	1.5 MHz/MI < 0.2
  Esaote	MyLabAlpha Portable	Contrast key On/off LVO choice	Touch screen/flash label	Contrast tuned imaging	1.5 MHz/MI < 0.2

   
  

  CHI , Contrast Harmonic Imaging; GEN , general harmonic frequency setting; LVO , left ventricular opacification; MI , mechanical index; PEN , lower fundamental frequency for harmonic imaging; VLMI , very low mechanical index (<0.2).

  
  

  ∗ Portable: defined as does not require wheels.

  
  

In recognition of the large volume of patients enrolled in prospective randomized studies, meta-analyses, registry data, and multicenter comparative effectiveness studies during rest and stress imaging, the Writing Group advises a class of recommendation (COR) and level of evidence (LOE) on diagnostic strategies using UEAs. The recommendations made are according to the updated 2015 American College of Cardiology/American Heart Association clinical practice guidelines as follows:

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  COR

  
  
  
  
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    Class I (strong): Benefits are much greater than risks. The procedure should be performed.

    
    
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    Class IIa (moderate): Benefits are greater than risks, and the procedure can be useful if performed.

    
    
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    Class IIb (weak): Benefits are slightly greater than risks, and the procedure might be reasonable to perform.

    
    
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    Class III: The procedures offers no benefit or is harmful if performed.

  
  
  
  
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  LOE

  
  
  
  
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    Level A: High-quality evidence from more than one randomized controlled trial (RCT), a meta-analysis of high-quality RCTs, or one or more RCTs corroborated by high-quality registry data

    
    
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    Level B-R: Moderate-quality evidence from one or more RCTs or a meta-analysis of moderate-quality RCTs

    
    
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    Level B-NR: Moderate-quality evidence from one or more well-designed nonrandomized trials, observational studies, or registry studies or meta-analysis of such studies

    
    
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    Level C-LD: Randomized or nonrandomized observational or registry studies with limitations in design or execution or a meta-analysis of such studies

    
    
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    Level C-EO: Consensus based on clinical experience

  
  

This update focuses on the new data that have been published and how these data, when combined with the 2008 consensus statement and 2014 ASE contrast sonography guidelines, have led to specific recommendations for UEA use in different clinical settings.

II

Comparing UEAs

Unlike red blood cells, which are poor scatterers of ultrasound, the microbubbles that compose UEAs are compressible and are of different density. This unique physical characteristic of microbubbles is important in understanding the behavior microbubbles exhibit when exposed to ultrasound energy. Currently there are three commercially available UEAs worldwide for cardiac imaging: Optison, Definity (Luminity in Europe), and Lumason (SonoVue outside the United States). Optison is available only in the United States and Europe, whereas Definity is marketed in the United States, Canada, Europe, Australia, and parts of Asia. Lumason is approved throughout North America, New Zealand, Europe, Brazil, and Asia. The range of bubble sizes permits passage through the pulmonary circulation (1.1–4.5 μm in diameter). All contain a high–molecular weight gas that improves their persistence because of reduced solubility and diffusivity. Both Optison and Definity contain perflutren (octofluoropropane) gas, with the main difference being the flexible shell composition. The Optison shell is made up of human serum albumin, whereas Definity uses a phospholipid shell. Lumason consists of a sulfur hexafluoride gas core with a phospholipid shell ( Table 3 ). The specific fatty acid chain length and charge, as well as the composition and length of the polyethylene glycol spacer, differ between Lumason and Definity. Optison and Definity require refrigeration before use, whereas Lumason is stored as a dry powder without refrigeration. Preparation requirements for each of the agents differ: Definity requires activation with a mechanical agitator, Optison requires a resuspension of the bubbles by hand, and Lumason requires hand agitation.

Although Optison and Definity have been given as 10% and 3% to 5% diluted infusions in normal saline (Appendix), Lumason has been primarily used in the United States as small 0.5-mL bolus injections followed by slow 5- to 10-mL saline flushes to avoid LV cavity shadowing. Because the Lumason vial contains 5 mL, these bolus injections can be repeated as needed to maintain homogenous cavity opacification.

There are other less widely available or developing UEAs. Sonazoid is a microbubble with a perfluorobutane gas core in a phosphatidylserine shell that received regulatory approval in 2007 for imaging of liver and breast tumors in Japan and South Korea. In 2014, it was approved for focal liver lesion imaging in Norway.

Intravenous (IV) UEAs are currently approved in the United States by the FDA to enhance LVO in adults, although Lumason has also been approved for pediatric use and for liver imaging. Although not specifically approved for stress testing, UEAs have been shown to improve the detection of RWM abnormalities at rest and during stress testing. All three approved UEAs have been shown to have excellent safety profiles.

II

Comparing UEAs

Unlike red blood cells, which are poor scatterers of ultrasound, the microbubbles that compose UEAs are compressible and are of different density. This unique physical characteristic of microbubbles is important in understanding the behavior microbubbles exhibit when exposed to ultrasound energy. Currently there are three commercially available UEAs worldwide for cardiac imaging: Optison, Definity (Luminity in Europe), and Lumason (SonoVue outside the United States). Optison is available only in the United States and Europe, whereas Definity is marketed in the United States, Canada, Europe, Australia, and parts of Asia. Lumason is approved throughout North America, New Zealand, Europe, Brazil, and Asia. The range of bubble sizes permits passage through the pulmonary circulation (1.1–4.5 μm in diameter). All contain a high–molecular weight gas that improves their persistence because of reduced solubility and diffusivity. Both Optison and Definity contain perflutren (octofluoropropane) gas, with the main difference being the flexible shell composition. The Optison shell is made up of human serum albumin, whereas Definity uses a phospholipid shell. Lumason consists of a sulfur hexafluoride gas core with a phospholipid shell ( Table 3 ). The specific fatty acid chain length and charge, as well as the composition and length of the polyethylene glycol spacer, differ between Lumason and Definity. Optison and Definity require refrigeration before use, whereas Lumason is stored as a dry powder without refrigeration. Preparation requirements for each of the agents differ: Definity requires activation with a mechanical agitator, Optison requires a resuspension of the bubbles by hand, and Lumason requires hand agitation.

Although Optison and Definity have been given as 10% and 3% to 5% diluted infusions in normal saline (Appendix), Lumason has been primarily used in the United States as small 0.5-mL bolus injections followed by slow 5- to 10-mL saline flushes to avoid LV cavity shadowing. Because the Lumason vial contains 5 mL, these bolus injections can be repeated as needed to maintain homogenous cavity opacification.

There are other less widely available or developing UEAs. Sonazoid is a microbubble with a perfluorobutane gas core in a phosphatidylserine shell that received regulatory approval in 2007 for imaging of liver and breast tumors in Japan and South Korea. In 2014, it was approved for focal liver lesion imaging in Norway.

Intravenous (IV) UEAs are currently approved in the United States by the FDA to enhance LVO in adults, although Lumason has also been approved for pediatric use and for liver imaging. Although not specifically approved for stress testing, UEAs have been shown to improve the detection of RWM abnormalities at rest and during stress testing. All three approved UEAs have been shown to have excellent safety profiles.

III

Recommendations for Imaging of UEAs

The signals obtained from UEAs are dependent on the MI of the transmitted ultrasound. The MI is directly related to the peak negative pressure and inversely related to the square root of the transmitted frequency. At a very low MI (VLMI) of <0.2, microbubbles begin to oscillate in an asymmetric manner, as the expansion phase is larger than the compression phase, generating an acoustic signal that is nonlinear in nature. A further increase in amplitude of the transmit wave may cause discontinuities in the microbubble shell as the oscillations become more exaggerated, effectively releasing the free gas to dissolve into the circulation. Additionally, gas can be driven out during compression of the microbubble, known as acoustically driven diffusion. The nonlinear acoustic signal distinction is essential to allow effective differentiation of surrounding tissue signal from microbubble signal.

As per the 2014 ASE contrast sonography guidelines, VLMI represents multipulse cancelation sequences that are most effective at MI values <0.2, low MI represents harmonic imaging techniques that are used at MI values <0.3, intermediate MI represents harmonic imaging techniques used at MIs of 0.3 to 0.5, and high MI is any MI that exceeds 0.5. Real-time VLMI techniques are available on nearly all commercially available ultrasound imaging systems. These pulse sequence schemes permit the enhanced detection of microbubbles within the LV cavity and myocardium and thus permit improved RWM and perfusion analysis. The pulse sequence diagrams of available multipulse VLMI imaging techniques were published in Table 1 and Figure 1 of the 2014 ASE contrast sonography guidelines. Pulse inversion (or phase inversion) is a tissue cancelation technique that delivers ultrasound pulses of alternating polarity (phase). Although pulse inversion provides excellent suppression of surrounding noncardiac tissue and results in high resolution by receiving only even-order harmonics, there is significant ultrasound signal attenuation, especially in basal myocardial segments of apical views in part because of filtering at higher frequencies. Power modulation (or amplitude modulation) detects fundamental and/or harmonic nonlinear activity almost exclusively from microbubbles when used at an MI < 0.2. This technique is also a multipulse cancelation technique, which varies the power, or amplitude, of each pulse, rather than the polarity. For example, at an MI of 0.05, both microbubbles and tissue respond in a linear fashion to the ultrasound pulse, whereas at twice this power (0.1), there is still a linear response from tissue but a nonlinear response from microbubbles. The linear responses from the two different pulses (the twice-amplified 0.05-MI response and the 0.1-MI response) can be subtracted from each other, thereby displaying only nonlinear behavior from the microbubbles. Although an increase in contrast enhancement is produced, this sequence scheme theoretically has reduced resolution and image quality compared with pulse or phase inversion imaging (which detects only higher frequency harmonic responses). Manufacturers have also combined these multipulse techniques by using both interpulse phase and amplitude modulation, which although more complex has the purpose of further enhancing nonlinear activity from microbubbles at a VLMI and canceling out the linear responses from surrounding tissue. The advantage of the VLMI imaging techniques, compared with B-mode low-MI harmonic imaging, is that there is better tissue cancelation, greater signal-to-noise ratio (sensitivity for detecting agent), and less microbubble destruction because of the lower MI required. The overall clinical effect of VLMI imaging techniques is to provide high spatial and reasonable temporal resolution that permits the simultaneous assessment of MP and wall motion, which is especially important in detecting coronary artery disease (CAD; Videos 1 and 2 ; available at www.onlinejase.com ). Because they detect the nonlinear activity at the fundamental frequency, power modulation and interpulse phase and amplitude modulation pulse sequence schemes have less attenuation and better microbubble contrast signal, resulting in improved apical and basal segment visualization ( Videos 3 and 4 ; available at www.onlinejase.com ). Specific instructions on optimizing image quality are given in Table 2 of the 2014 sonographer update.

Continuous intermediate (MIs of 0.3 of 0.5) or high-MI imaging should be avoided because it causes destruction of microbubbles and creates swirling artifacts. However, brief (five to 15 frames) high-MI impulses (MIs of 0.8 to 1.2), which have been termed “flash impulses,” can be used during VLMI imaging to clear contrast from the myocardium and enhance the delineation of endocardial borders. As discussed in detail later, the rate of myocardial contrast replenishment following the high-MI flash impulse has been used in combination with the plateau myocardial contrast intensity to assess MP.

As outlined in the 2008 ASE consensus statement and 2014 ASE guidelines for sonographers, Doppler enhancement of left- and right-sided Doppler signals can be achieved with UEAs, and this has been useful for both adult and pediatric applications. Although there are no new clinical studies formally evaluating this, the guidelines committee continues to strongly recommend their use for enhancement of tricuspid regurgitant peak velocity jet detection (for right ventricular pressure estimates) and peak velocity measurements in valvular stenosis evaluation. This is particularly relevant when the UEAs are being used for imaging indications, especially because the threshold for the detection of microbubbles by Doppler is lower than that for imaging indications. When performing these measurements, the Doppler gain signals should be lowered from unenhanced echocardiography settings, to a level that reduces “microbubble noise” and improves the resolution of the Doppler profile. As emphasized in the 2008 guidelines, the most distinctly enhancing spectra should be measured at a lowered gain setting to reduce blooming artifact.

IV

Clinical Applications

Since the 2008 ASE consensus statement, numerous publications have reinforced existing applications or emphasized new applications for ultrasound enhancement. This section will provide an update on these specific clinical applications and recommendations for their use.

IV.A

Update on Quantification of LV Volumes, LVEF, and RWM

According to the recent ASE/European Association of Cardiovascular Imaging recommendations for LV chamber quantification, volumetric measurements should be based on tracings at the interface of the compacted myocardium and the LV cavity. However, trabeculations in the apical region, as well as artifacts from adjacent lung tissue and noise, can make it difficult to track this interface. After injection of ultrasound contrast agent, the opacified blood in the left ventricle fills the spaces among the LV trabeculations up to the compacted myocardium, allowing more accurate and reproducible tracings to be performed. All three contrast agents commercially available for LVO have been extensively evaluated in large multicenter trials.

LV Volumes

Defining normal values for LV size is important for prognosis in a spectrum of clinical diagnoses, including cardiomyopathy and valvular heart disease. Quantification of LV volumes is not a straightforward task and can depend on many factors, including populations studied and imaging methods. Current ASE guidelines for cardiac chamber quantification provide recommended standards for reporting LV internal diameters derived from the parasternal long-axis view, LV volumes by a biplane method, and normalization to body surface area ; use of UEAs is advised if this information cannot be readily obtained because of the poor quality of endocardial visualization. LV internal dimension measurements may underestimate the degree of LV enlargement compared with volume determination by biplane contrast. Furthermore, unenhanced two-dimensional (2D) echocardiography may underestimate LV volumes because of foreshortening, exclusion of the portion of the left ventricle within noncompacted trabecular surfaces, and inadequate visualization of the endocardium. Use of UEAs may overcome these technical errors by allowing the true longitudinal axis of the left ventricle to be measured, as well as enabling accurate tracing of endocardial borders by detection of intratrabecular blood volume and clear delineation of the endocardial border ( Figure 1 ), resulting in a closer correlation with cardiac magnetic resonance imaging (CMRI). LV volumes measured with unenhanced echocardiography are also consistently smaller than those derived from CMRI. In a recent multicenter study, end-diastolic volume measurements determined by enhanced echocardiography were significantly larger than those without UEAs, irrespective of 2D or three-dimensional (3D) echocardiographic techniques. However, there are currently no established values for normal LV volumes in enhanced echocardiography, as enhanced studies in large populations without cardiac disease or indications for contrast echocardiography are not feasible. An early study examining baseline prechemotherapy echocardiograms on female patients with breast cancer classified 51% of contrast-enhanced end-diastolic volume as abnormal, even though LV dimensions were within the normal range by unenhanced 2D volume measurements. To account for this change in the normal range when using UEAs for volume measurements, the authors proposed an end-diastolic volume upper limit cutoff of 83 mL/m ² for women and 98 mL/m ² for men. Using ±2 SDs from the mean of enhanced volumes as normal also resulted in better agreement with CMRI than that of noncontrast volumes. The Writing Group emphasizes the need for larger prospective studies to define ranges for LV volumes observed with UEAs and VLMI imaging.

Differences in end-diastolic and end-systolic volumes observed in the same patient without contrast ( top ) and with UEAs and low-MI imaging ( bottom ). Top row , left to right : Precontrast LV quantification of end-diastolic volume (306 mL) and end-systolic volume (246 mL) for estimation of LVEF. Bottom row , left to right : Postcontrast LV quantification of end-diastolic volume (391 mL) and end-systolic volume (308 mL) for estimation of LVEF. A marked increase in volume size is noted after contrast.

Left Ventricular Ejection Fraction

The quantitative assessment of LVEF becomes particularly important when patients are considered for a defibrillator or cardiac resynchronization therapy, as well as in the follow-up of cardiotoxicity from chemotherapeutic agents or the evaluation of patients with valve disease for intervention (e.g., aortic and mitral regurgitation). In these circumstances, reproducibility is of critical importance. Several studies have demonstrated that when comparing unenhanced with enhanced cardiac ultrasound, and using CMRI as the gold standard, the accuracy of determination of LVEF was improved with UEA. Multicenter studies have confirmed that in comparison with unenhanced echocardiography, interobserver variability was significantly reduced with UEAs, resulting in similar intraclass correlation coefficients as seen with CMRI. Although unenhanced 3D echocardiography has improved the reproducibility and reliability of serial ejection fraction measurements (as in the case of cancer chemotherapy), the use of UEAs in this setting has not further improved test-retest variability. However, VLMI imaging techniques have not been available for 3D acquisitions.

Regional Wall Motion

Analysis of RWM is subject to significant interobserver variability. Inherently, wall motion is a subjective assessment without a gold standard and is in part dependent on image quality, highlighting the importance of being able to accurately detect the endocardium throughout systole. It is also important to note that visual wall motion assessment relies on evaluation of wall thickening, and thus both the endocardium and epicardium must be identified. A multicenter study has demonstrated that interobserver agreement for RWM was highest in patients who underwent enhanced echocardiography compared with unenhanced echocardiography and CMRI. This same group of investigators found that UEAs significantly improved the agreement for RWM over nonenhanced echocardiography compared with CMRI. In this study, 3D-enhanced echocardiography did not show any incremental value over 2D-enhanced echocardiography in the detection of RWM abnormalities. Similarly, the use of echocardiographic enhancement during stress has been shown to improve visualization of LV segments, interpretation confidence, sensitivity, and specificity in technically challenging and obese patients. Although the Writing Group does not recommend UEA use where the heart cannot be imaged because of chest deformity or lung hyperexpansion, UEAs should be used for RWM analysis whenever the appropriate views can be obtained but endocardial border delineation is inadequate for interpretation.

• 1.
  

  As per 2008 ASE guidelines, for routine resting echocardiographic studies, UEAs should be used when two or more LV segments cannot be visualized adequately for the assessment of LV function (LVEF and RWM assessment) and/or in settings in which the study indication requires accurate analysis of RWM. (COR I, LOE A).

  
  
• 2.
  

  A brief (5- to 10-frame) high-MI (0.8–1.2) “flash” impulse can be used with VLMI imaging to clear myocardium of contrast and improve endocardial border delineation for volume and ejection fraction measurements (COR IIa, LOE C-EO).

  
  
• 3.
  

  Ultrasound enhancement should be used in all patients in whom quantitative assessment of LVEF is important to prognosis or management of the clinical condition. VLMI and low-MI harmonic imaging techniques should be used to provide optimal LVO (COR I, LOE B-R).

  
  
• 4.
  

  LV volumes obtained by enhanced echocardiography are typically larger than those measured without UEAs, and therefore 2015 ASE chamber quantification guidelines should be applied with caution when determining normal ranges. Although the normal range for LVEF does not appear to be different, new reference ranges for end-diastolic and end-systolic LV volumes when using UEAs should be established.

  
  
• 5.
  

  As per section III of the 2014 ASE guidelines for sonographers, a continuous infusion or a low volume (≤0.5 mL) bolus injection with slow (10–20 sec) saline flush is recommended along with VLMI imaging to minimize apical microbubble destruction and basal segment attenuation.

Key Points and Recommendations

IV.B

Update on Intracardiac Abnormalities

There are specific areas in which prior guideline documents have recommended UEAs for intracardiac abnormalities. The 2016 ASE guidelines for the use of echocardiography in evaluation for a cardiac source of embolism recommend the use of UEAs “to assist in border definition and check for vascularization” of intracardiac thrombi or masses and consider as “potentially useful” the application of UEAs to aid in detection of left atrial and appendage thrombi (discussed later) and differentiation of avascular thrombi from vascular tumors. The 2011 ASE clinical recommendations for multimodality cardiovascular imaging of patients with hypertrophic cardiomyopathy affirm that transthoracic echocardiography (TTE) combined with the IV injection of a UEA should be performed in patients with hypertrophic cardiomyopathy with suspected apical hypertrophy, to define the extent of hypertrophy and to diagnose associated potential complications of apical aneurysms and thrombi. This document also outlines the specific protocol for septal perforator injections of diluted UEAs to delineate the perfusion territory of each perforator (section G.ii). Other clinical studies have been published that highlight these specific applications and support broader guidelines for UEA use.

Intracardiac Thrombi

Intracardiac thrombi pose serious clinical risks, including systemic embolization with potential catastrophic consequences; likewise, treatment with antithrombotic agents can also impose significant risk, and their use must be appropriately justified. Therefore, accurate detection and diagnostic management of cardiac thrombi is essential. Despite advances in other imaging modalities, echocardiography remains the initial tool for diagnosis and risk stratification in patients predisposed to developing cardiac thrombi. The use of UEAs facilitates LV thrombus detection by providing opacification within the cardiac chambers to demonstrate the “filling defect” appearance of an intracardiac thrombus ( [CR] ; available at www.onlinejase.com ). Furthermore, perfusion echocardiography can provide an assessment of the tissue characteristics of identified LV masses by differentiating an avascular thrombus from a tumor, resulting in improved diagnostic performance of echocardiography. Although delayed enhancement CMRI has the highest sensitivity and specificity for detection of LV thrombi, performance of echocardiography with a UEA is a more clinically feasible initial test. However, CMRI should be considered when a UEA with VLMI fails to detect an intracardiac thrombus but clinical suspicion persists.

Intracardiac Masses

Two-dimensional echocardiography is usually the primary initial diagnostic imaging modality offering real-time, high spatial and temporal resolution evaluation of cardiac masses. Although numerous echocardiographic criteria have been developed to define cardiac masses, diagnostic errors and misclassifications can lead to unnecessary surgery or inappropriate anticoagulation. The judicious use of UEAs to characterize cardiac masses and integrate all the information to establish etiologies may potentially avoid these diagnostic errors. Intracardiac masses can be a normal variant of cardiac structure such as a false chord, accessory papillary muscle, or heavy trabeculation or can be pathologic such as thrombus, vegetation, or tumor. Any suspicious cardiac mass, when not clearly evident on baseline images, can be confirmed or refuted after injection of IV UEAs for better delineation of structures. Just as with unenhanced echocardiography, off-axis images and longer loop acquisitions may be required to identify and characterize intracardiac thrombi or masses.

Echocardiographic perfusion imaging using VLMI with intermittent-flash (high-MI) technique has been demonstrated to characterize vascularity of cardiac masses and assist with the differentiation of malignant, highly vascular tumors from benign tumors or thrombi. This characterization is supported by the qualitative and quantitative differences between the levels of perfusion (enhancement) in various types of cardiac masses and comparison with adjacent myocardium. The qualitative approach includes the visual inspection of rate of contrast replenishment within the mass following a high-MI impulse and descriptively categorized as lack of enhancement, partial or incomplete enhancement, or complete enhancement. Most malignancies have abnormal neovascularization that supplies rapidly growing tumor cells, often in the form of highly concentrated, dilated vessels. Thus, complete enhancement or hyperenhancement of the tumor (compared with the surrounding myocardium) supports the existence of a highly vascular tumor, which is most often malignant. Stromal tumors, such as myxomas, have a poor blood supply and appear partially enhanced ( [CR] , Figure 2 ; available at www.onlinejase.com ), while thrombi or papillary fibroelastoma are generally avascular and show no enhancement. The level of enhancement has been shown to correlate with the pathologic diagnosis or with resolution of the mass after anticoagulant therapy. However, potential pitfalls exist that may contribute to the appearance of partial enhancement of avascular structures in the far field. Therefore, it is recommended that perfusion imaging be done in views that allow near-field visualization of microbubble replenishment following high-MI impulses. Several investigations since the 2008 ASE contrast document have confirmed the differences in maximum acoustic intensity and mass-replenishing velocity following high-MI impulses during VLMI for various pathologies.

Modified apical four-chamber images of intracardiac masses in patients receiving continuous UEA infusion. All images were obtained at plateau intensity before a high-MI impulse. The left panel exhibits no enhancement, consistent with thrombus. The middle panel exhibits a small amount of enhancement (less than myocardial) and was a myxoma. The mass in the right ventricle in the right panel was hypervascular (similar to myocardial plateau enhancement) and was a metastatic renal cancer (see [CR] ; available at www.onlinejase.com ).

Apical Abnormalities in Patients with Hypertrophic Cardiomyopathy

The apical variant is present in about 7% of patients with hypertrophic cardiomyopathy but may not be detected by routine TTE, because of incomplete visualization of the apex. When apical hypertrophic cardiomyopathy is suspected but not clearly documented or excluded, contrast studies should be performed. If apical hypertrophic cardiomyopathy is present, the characteristic spade-like appearance of the LV cavity in diastole, with marked apical myocardial wall thickening, is clearly evident on enhanced images. Complications associated with apical hypertrophy can also be readily visualized, such as apical aneurysm formation and thrombi ( Figure 3 , [CR] ; available at www.onlinejase.com ). The presence of an apical aneurysm has recently been associated with adverse outcomes, including arrhythmic events and thromboembolism. However, some pitfalls can be encountered, leading to false-negative echocardiographic findings, as is the case in smaller apical aneurysms, or if contrast-specific imaging machine settings are not optimized, as was reported in a recent study comparing enhanced echocardiography with CMRI. Because VLMI imaging permits better apical delineation, it is recommended that UEAs be routinely used with VLMI imaging in evaluating patients with hypertrophic cardiomyopathy ( [CR] ; available at www.onlinejase.com ). Adjustment of the transmit focus to an apical position may reduce scan line density and UEA destruction, further improving apical image resolution.

Apical four-chamber end-systolic images of a patient with apical hypertrophic cardiomyopathy. Unenhanced images ( left ) fail to delineate endocardial border, but VLMI images during a continuous infusion of a UEA ( right ) demonstrated apical hypertrophy in October 2014. Over approximately 2 years, VLMI imaging detected the interval development of an apical aneurysm. The patient subsequently had an implantable defibrillator placed.

Noncompaction Cardiomyopathy

Noncompaction of the myocardium is an uncommon but increasingly recognized abnormality that can lead to heart failure, arrhythmias, cardioembolic events, and death. It is due to alterations of myocardial structure with thickened, hypokinetic segments that consist of two layers: a thin, compacted subepicardial myocardium and a thicker, noncompacted subendocardial myocardium. Enhanced echocardiographic studies may be helpful in identifying the characteristic deep intertrabecular recesses by showing microbubble-filled intracavitary blood between prominent LV trabeculations when LV noncompaction is suspected but inadequately seen by conventional 2D imaging ( Figure 4 ). It may be useful to use an MI that is somewhat higher than VLMI (e.g., increase to 0.3–0.4) to better distinguish the myocardial trabeculations in the noncompacted myocardium from UEA presence within the deep recesses. This higher MI at real-time frame rates destroys the low-velocity microbubbles within the trabecular myocardium before they can replenish, while the higher velocity intertrabecular microbubbles in the LV cavity can replenish, permitting better delineation of the noncompacted layer ( Figure 4 ).

Apical four- and two-chamber (A4C and A2C) views at end-diastole in a patient with unexplained cardiomyopathy. VLMI imaging demonstrated LV cavity and myocardial opacification, but real-time B-mode harmonic imaging at a slightly higher MI ( middle ) resulted in destruction of trabecular myocardial microbubbles and better delineation of the noncompacted layer ( arrows ). The noncompaction thickness in this intermediate-MI real-time harmonic imaging mode correlated closely with that seen at magnetic resonance imaging ( right ).

Post–Myocardial Infarction Complications

LV aneurysm, an often asymptomatic complication of a prior myocardial infarction, is a common apical LV abnormality. True aneurysms are characterized by thin walls and a dilated apex, which may be akinetic or dyskinetic and involve the full thickness of the ventricular wall. These findings are usually seen easily on unenhanced echocardiographic imaging. However, if the apex is not completely visualized, an apical aneurysm may go undetected until a UEA is used. LV pseudoaneurysm, free wall rupture, and post–myocardial infarction ventricular septal defects pose life-threatening risks to patients and can usually be detected by unenhanced echocardiography. However, patients may have suboptimal studies because of anatomy or position, or both, and clinical conditions (e.g., being supine and intubated in the critical care unit) that limit the attainment of an optimal view of the apex. UEAs may be essential in establishing the diagnosis, as well as detecting further associated complications, such as LV thrombus.

Right Ventricular Assessment

Although agitated-saline enhancing agents can be used to visualize abnormalities in the right-sided chambers, the contrast effect is of short duration. When persistent enhancement of the right ventricular endocardial borders is necessary, commercially available UEAs have been used to show various abnormalities of right ventricular morphology, including focal RWM abnormalities, tumors, and thrombi. The UEAs can also be used to distinguish these abnormalities from normal structures, such as prominent trabeculations or the moderator band. In this setting, parasternal views, or a modified apical four-chamber window of right ventricle, may be optimal to place the right ventricle into the near field.

Atria and Left Atrial Appendage

UEAs have also been used to show anatomic features of the atria, especially the left atrial appendage, more clearly and can be useful in differentiating thrombi from artifacts, dense spontaneous echocardiographic contrast, or normal anatomic structures. Differentiation of artifacts from thrombus is especially important in the setting of precardioversion transesophageal echocardiography (TEE). A prospective study of 100 patients undergoing precardioversion TEE demonstrated that UEAs provided improved identification of left atrial appendage filling defects and differentiation from artifacts, resulting in an increased level of confidence for thrombus exclusion before cardioversion. Moreover, in another prospective case-control comparison study of 180 patients in atrial fibrillation undergoing cardioversion, no embolic events occurred in the group that was imaged with UEAs during precardioversion TEE, while three events occurred in a control group. The authors concluded that in patients with atrial fibrillation planned for cardioversion, contrast enhancement renders transesophageal echocardiographic images more interpretable, facilitates the exclusion of atrial thrombi, and may reduce the rate of embolic adverse events. Specific MI settings were not provided in these studies, but it is likely that at frequencies used in TEE, an MI < 0.5 and harmonic mode will be optimal for UEA delineation.

• 1.
  

  Ultrasound enhancement should be used in patients in whom LV thrombus cannot be ruled in or out with noncontrast echocardiography (COR I, LOE B-NR).

  
  
• 2.
  

  Ultrasound enhancement should be considered in patients in whom structural abnormalities of the left ventricle (noncompaction cardiomyopathy, apical hypertrophy and aneurysms) cannot be adequately assessed with noncontrast echocardiography (COR IIa, LOE B-NR).

  
  
• 3.
  

  Ultrasound enhancement should be used for ruling in or out an LV pseudoaneurysm (COR I, LOE B-NR).

  
  
• 4.
  

  Ultrasound enhancement with VLMI imaging should be used in the differential diagnosis of cardiac masses by assessing the vascularity of the mass (COR IIa, LOE B-NR).

  
  
• 5.
  

  Ultrasound enhancement should be considered during TEE whenever the atrial appendage has significant spontaneous contrast or cannot be adequately visualized with unenhanced imaging (COR IIa, LOE B-NR).

Key Points and Recommendations for the Use of UEAs in Detecting LV Cavity Abnormalities and Intracardiac Masses

IV.C

Stress Echocardiography

Left Ventricular Opacification

LVO with low-MI harmonic imaging has been demonstrated to be integral in the achievement of more accurate and efficient stress echocardiographic testing. The use of UEAs during both exercise and dobutamine stress echocardiography (DSE) improves sensitivity, specificity, and diagnostic accuracy to a greater extent in patients with suboptimal versus optimal imaging windows. This improvement in accuracy has been attributed to the ability to visualize all regional wall segments, making it equivalent to the accuracy of optimal unenhanced studies in which all segments can be visualized. In 839 consecutive patients undergoing stress echocardiography, the addition of UEAs with VLMI imaging during stress echocardiography improved endocardial border detection at rest and peak stress, yielding 99.3% efficacy in achieving diagnostic study quality, thereby improving reproducibility and reader confidence in interpretation. This has translated into a significant impact on accuracy, especially when the unenhanced image confidence was low or there were more than two segments not well visualized without contrast.

Decision algorithms in which contrast imaging enhancement is used when two or more segments are not adequately visualized, beginning at rest and repeated at peak stress, produce a cost savings with abnormal testing predicting mortality and adverse events. Compared with exercise electrocardiography (ECG) and nuclear testing, UEA use results in fewer downstream tests, which correlates with significantly lower costs.

Although the VLMI multipulse sequence schemes were available on most manufacturing systems as detailed in the 2008 ASE consensus statement, only recently have manufacturers begun using them for LVO. The VLMI techniques were initially designed for MP assessment, but their sensitivity for microbubble detection and complete apical cavity opacification without swirling artifact has improved stress LVO imaging. Both multicenter and prospective single-center studies have demonstrated the effectiveness of VLMI imaging to detect RWM abnormalities. In addition to enhanced sensitivity and apical delineation, the VLMI techniques detect subendocardial wall thickening abnormalities that may otherwise go undetected if one were examining transmural wall thickening during demand stress. The combination of LVO and subepicardial layer enhancement during replenishment following high-MI impulses helps delineate the subendocardium and analysis of wall thickening just at this location ( Figure 5 , [CR] ; available at www.onlinejase.com ). The integration of UEAs with VLMI imaging for the evaluation of wall thickening and ischemia into the routine evaluation of patients with left bundle branch block during DSE has been shown to improve the detection of CAD and independently predict mortality and cardiovascular events.

Subendocardial perfusion defect and subendocardial wall thickening abnormality ( arrows ) that is not seen when contrast was opacifying only the LV cavity and not the subepicardium ( left ). During myocardial contrast replenishment, the subendocardial perfusion defect ( arrows ) delineates the subendocardial wall thickening abnormality (see [CR] ; available at www.onlinejase.com ).

On the basis of these studies, it is apparent that UEAs improve the diagnostic accuracy of RWM analysis at rest and during stress imaging. VLMI imaging appears to be optimal for RWM analysis, in that the added perfusion data assist in the differentiation of subtle wall thickening abnormalities due to subendocardial ischemia. This appears to be helpful in all coronary artery territories and may be especially helpful in segments that are frequently difficult to visualize ( Figure 6 , Videos 4 and 7 ; available at www.onlinejase.com ). Because disease in a coronary artery territory may affect only one segment in any particular apical or parasternal view, the Writing Group recommends that UEAs be used for LVO whenever any segment cannot be adequately visualized.

End-diastolic (ED; left ), and end-systolic (ES; right ) in the apical two-chamber view, demonstrating how only VLMI imaging with UEAs can completely delineate a basal to mid inferior wall thickening abnormality. Because VLMI imaging is done with power modulation, fundamental nonlinear responses are detected, resulting in less basal segment attenuation compared with low-MI imaging ( middle ) which are attenuated because they are harmonic frequency signals. See [CR] , available at www.onlinejase.com .

Perfusion Imaging during Inotropic or Exercise Stress

MP imaging has been used in a variety of circumstances for the assessment of myocardial ischemia and viability. VLMI imaging with IV infusions or small bolus injections of UEAs has been used to examine myocardial blood flow and volume at frame rates of 20 to 30 Hz. This has been termed real-time MCE (RTMCE). Brief high-MI impulses are administered to clear myocardial contrast, following which replenishment is analyzed on the end-systolic images ( Videos 8 and 9 ; available at www.onlinejase.com ). This technique has been performed clinically in thousands of patients during dobutamine stress or with treadmill or bicycle exercise.

In the setting of DSE, perfusion analysis has improved CAD detection compared with wall motion analysis alone. The improvement appears to be related to the ischemic cascade, in which perfusion abnormalities have been shown to occur before wall motion abnormalities during demand ischemia. As discussed in the previous section, another factor leading to improved sensitivity with VLMI imaging is the detection of subendocardial wall thickening abnormalities when using perfusion enhancement ( Figure 5 ). This has been evident primarily in DSE, where transmural wall thickening may appear normal despite the existence of a subendocardial wall thickening abnormality unmasked by the subendocardial perfusion defect ( [CR] ; available at www.onlinejase.com ).

The 20- to 30-Hz frame rates with VLMI imaging have permitted sonographers and physicians trained in basic echocardiography to adapt to this technique, whether they are using UEAs to enhance RWM analysis, assess global systolic function, or analyze perfusion. The higher spatial resolution of perfusion echocardiography, compared with radionuclide imaging or positron emission tomography, has permitted improved detection of ischemia at rest and during stress. It may also be useful in patient populations with resting nonischemic wall motion abnormalities such as ventricular paced rhythms or left bundle branch block. Adding perfusion information to RWM analysis has resulted in better defining the extent of CAD that exists and is better than RWM analysis alone in identifying those at risk for subsequent cardiac events.

Perfusion abnormalities during demand stress have been correlated with fractional flow reserve measurements using invasive hemodynamics in patients with intermediate angiographic stenosis between 50% and 80% in diameter. Here the correlations are not good and reflect differences in what the two techniques are measuring. Fractional flow reserve is determined by measuring a pressure gradient across a given stenosis during hyperemic stress in the catheterization laboratory and does not take into account the impact of capillary resistance, which has been shown to be the major regulator of coronary blood flow during stress. Because RTMCE measures capillary blood velocity and blood volume, stress-induced abnormalities may exist before detection of significant hyperemic pressure changes across a stenosis in the 50% to 80% range. These differences appear to be clinically relevant, and further investigation into their prognostic significance is needed.

Since the publication of the 2008 ASE contrast document, the incremental value of MP imaging over wall motion analysis alone in predicting patient outcomes has been demonstrated with bicycle exercise echocardiography, treadmill exercise echocardiography, and DSE. This includes RCTs comparing conventional stress echocardiography (in which UEAs were used only for the current FDA-approved indication) with RTMCE. In each of these settings, delayed replenishment of contrast during a continuous infusion of microbubbles was seen in a significant percentage of patients in the absence of RWM abnormalities and appeared to be independently predictive of subsequent death and nonfatal myocardial infarction.

Perfusion Imaging during Vasodilator Stress

Since the publication of the last 2008 ASE consensus statement regarding the use of UEAs in the context of echocardiography, many pertinent studies have reported on feasibility, safety, diagnostic and prognostic accuracy of RTMCE in the assessment of MP imaging, specifically during vasodilator stress echocardiography, strengthening the evidence toward the use of such vasodilator stress modality in conjunction with RTMCE. Vasodilator stress perfusion imaging appears to provide equivalent information for detection of CAD compared with inotropic stress, with advantages of rapid performance and possibly better image quality due to the lower heart rate (often not exceeding 100 beats/min) and less translational cardiac movement ( Figure 7 ). However, conventional detection of stress-induced RWM abnormalities may in some cases be less sensitive because the mode of stress does not depend on myocardial oxygen demand. Several vasodilators have been used in studies with RTMCE, namely, adenosine, dipyridamole, and, more recently, regadenoson. Adenosine and dipyridamole are the most commonly used vasodilators for perfusion imaging. Both agents act nonselectively directly or indirectly to activate all four adenosine receptor subtypes (A1, A2A, A2B, and A3). This can result in chest pain, mild dyspnea, hypotension, bronchospasm, and, rarely, reversible atrioventricular nodal block. Regadenoson is a potent selective A2A agonist, administered as a 400-μg IV bolus, with rapid onset of action (within 30 sec) and adequate duration of action to allow sufficient time for image acquisition (up to 4 min) with less severe side effects, and it may evolve to be one of the vasodilators of choice for perfusion imaging ( Figure 8 ). Information from perfusion data is equivalent for all these vasodilators, and therefore the choice for each can be tailored on the basis of local availability, cost, side effects, and perceived practical advantages or disadvantages.

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