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New Applications in Echocardiography for Ultrasound Contrast Agents in the 21st Century

      Abstract

      Contrast echocardiography microbubbles are ultrasound-enhancing agents that were originally designed to help improve endocardial border definition, known as left ventricle opacification, and to enhance Doppler signals. Over time, contrast microbubbles are used to assess myocardial perfusion because they travel through the capillaries of the cardiac circulation. Current research provides good evidence that myocardial perfusion echocardiography improves comprehensive echocardiographic evaluations of ischemic heart disease. The approval of regulatory authorities and the availability of quantitative operator-independent analysis software will hopefully prompt physicians and sonographers to implement myocardial perfusion echocardiography into the daily workflow of echo laboratories. New diagnostic and therapeutic applications will result in improved patient care, especially in the area of sonothrombolysis, where preliminary data have already shown utilization in ST elevation myocardial infarction, improving left ventricular systolic function and reducing the need for implantable defibrillators at 6-mo follow-up. This review gives an overview of the applications of myocardial perfusion imaging with ultrasound. Each cited study had institutional review board/institutional animal care and use approval.

      Key Words

      Introduction

      Contrast echocardiography microbubbles are ultrasound-enhancing agents that were originally designed to help improve endocardial border definition, known as left ventricle (LV) opacification, and to enhance Doppler signals. In the 1990s, these enhancing agents were further developed, and specific contrast agents were designed to remain in the systemic circulation after venous injection (
      • Porter T.R.
      • Xie F.
      Visually discernible myocardial echocardiographic contrast after intravenous injection of sonicated dextrose albumin microbubbles containing high molecular weight, less soluble gases.
      ). At the same time, ultrasound imaging enhancement techniques developed (such as harmonic imaging) to also enhance LV opacification. The microbubbles of the contrast agents contain gases that are near-perfect reflectors of acoustic ultrasound energy. The liquid suspensions of stable, gas-filled microbubbles are used to enhance ultrasound images as they reflect ultrasound waves when they traverse the smallest human blood vessels, the capillaries, without disrupting the local environment. Accordingly, microbubble ultrasound contrast agents (UCAs) are clinically useful in enhancing ultrasound images and improving the accuracy of diagnoses. Also, these microbubbles are used to assess myocardial perfusion because they travel through the capillaries of the cardiac circulation. More recently, UCAs have been used to visualize the carotid artery vasa vasorum and neovascularization of atherosclerotic plaques, suggesting a new paradigm for analyzing the development of atherosclerosis and presenting new possibilities for developing treatment options. In addition, medications or genes may be attached to a UCA and subsequently used to deliver site-specific therapy to targeted organs in the body.

      Effect of Ultrasound on Contrast Agents

      The present generation of UCAs consists of microbubbles containing a hemodynamically inert gaseous core (e.g., octafluoropropane, sulfur hexafluoride) and a stabilizing outer shell (e.g., lipid, albumin or biopolymer), which oscillate under the influence of ultrasound waves. Similar to agitated saline, now in use for more than 35 y to determine cardiac and intrapulmonary shunts, these contrast echocardiography microbubbles form multiple small liquid air interfaces whose boundaries have a high acoustic impedance mismatch, resulting in enhanced ultrasound reflection. A major difference of contrast microbubbles compared to saline bubbles is the size that is approximately the same as of a red blood cell (RBC), with the bubbles small enough (1–8 μm) to traverse the pulmonary capillaries in order to enter the systemic circulation. With similar behavior and rheology to RBCs, they remain entirely within the vascular compartment and remain in circulation for approximately 3–5 min before they dissolve and lose their ability to produce ultrasound backscatter. Ultrasound microbubbles must be stable enough to resist destruction at low ultrasound power outputs and so maintain a sufficient concentration in the heart to give a satisfactory image. Various contrast agents are available, each having slightly different shell compositions and gas cores (Table 1 and Fig. 1). The echogenicity and ultrasound properties of the UCA are determined by the size, shell and compressibility of the shell and encapsulated gas that composes the microbubbles. Specific imaging techniques and software are required to perform myocardial contrast perfusion echocardiography to take advantage of the different ultrasound reflection properties of the contrast microspheres versus soft tissue. Ultrasound acoustic pressure is described as the mechanical index (MI) and corresponds to the power output of the scanner. With standard 2-D echocardiography imaging, the MI is ∼1.4; however, at this level the microspheres would oscillate to such a degree that they would burst and be destroyed. Therefore, very low MI (VLMI) (<0.2) imaging is used with contrast imaging. The oscillation effect of contrast echocardiography under low MI ultrasound means the ultrasound reflections are different for microbubbles compared with soft tissue. This difference can be harnessed to enhance contrast versus tissue differentiation when imaging: microbubbles reflect ultrasound in a non‐linear format compared with tissue, which reflects ultrasound in a linear manner. Non‐linear reflection means the sound waves are reflected not only at the frequency of the original ultrasound wave but also at higher, harmonic frequencies. Soft tissue, however, produces fewer harmonics, and hence reflects the ultrasound waves in a more linear fashion. Different methods are used by various vendors to take advantage of the specific reflection properties for tissue versus contrast microbubbles, including pulse inversion, power modulation and coherent contrast imaging. Power modulation and coherent contrast imaging are multi-pulse schemes that cancel soft tissue linear reflections and enhance fundamental non-linear reflections (Fig. 2). Therefore, fundamental non-linear imaging permits high sensitivity contrast imaging at the fundamental frequency, which reduces attenuation and allows for optimal perfusion imaging and left ventricular opacification of basal, mid and apical myocardial segments.
      Table 1Currently commercially available echocardiography contrast agents
      Gas coreShellTrade nameBubble size (μm)
      OctafluoropropaneAlbuminOptisonVR (GE Healthcare, Princeton, NJ, USA)1–10
      OctafluoropropaneLipidDefinityVR (Lantheus medical imaging, Billerica, MA, USA)1–10
      LuminityVR (Lantheus medical imaging, Billerica, MA, USA)
      Sulfur hexafluorideLipidSonovue (Bracco Imaging S.p.A, Milan, Italy)1–10
      PerfluorobutaneLipidSonazoid (GE Heakthcare, Princeton, NJ, USA)2–3
      Fig 1
      Fig. 1Examples of different ultrasound contrast agents and different shell properties. Also refer to the text for more examples.
      Fig 2
      Fig. 2Diagram of the relation between the power used at ultrasound studies and the backscatter frequency to explain the existence of second harmonics.

      Myocardial Perfusion Imaging

      Myocardial perfusion imaging has been used in a variety of circumstances for detecting myocardial ischemia during stress imaging (Fig. 3) and for detecting microvascular obstruction (Fig. 4, Fig. 5). Although high MI-triggered imaging (gated to end systole) was initially used for perfusion analysis, VLMI imaging using fundamental non-linear imaging has replaced this (
      • Rafter P.
      • Phillips P.
      • Vannan M.A.
      Imaging technologies and techniques.
      ), because it allows for simultaneous analysis of wall thickening and microvascular replenishment after brief (5–10 frames) high MI impulses to clear myocardium of contrast, with subsequent VLMI imaging to analyze replenishment. Perfusion imaging can be achieved with intravenous infusions or small bolus injections of UCAs. Although the contrast replenishment is analyzed in real time, the quantification of replenishment should be performed with images near end systole to avoid arteriolar contrast interference in the assessment of capillary replenishment (
      • Leong-Poi H.
      • Le E.
      • Rim S.J.
      • Sakuma T.
      • Kaul S.
      • Wei K.
      Quantification of myocardial perfusion and determination of coronary stenosis severity during hyperemia using real-time myocardial contrast echocardiography.
      ). The analysis of myocardial perfusion should be performed during a steady state concentration of microbubbles in the myocardium and LV cavity. The high MI impulse should be optimized to clear capillaries of contrast at or near end systole, but minimize LV cavity destruction, which would affect the input function. Replenishment at end or near end systole can then be analyzed visually based on what we know about capillary blood flow (
      • Wei K.
      • Le E.
      • Bin J.P.
      • Coggins M.
      • Jayawera A.R.
      • Kaul S.
      Mechanism of reversible (99 m)Tc-sestamibi perfusion defects during pharmacologically induced vasodilatation.
      ). This typically fits a 1-exponential function, and based on capillary blood flow physiology and the elevation plane of the destruction high MI beam, there should be replenishment within approximately 4 seconds under resting conditions and 2 seconds during hyperemic stress (Table 2). This visual method of analysis has been performed clinically in thousands of patients during dobutamine stress, bicycle stress, treadmill stress, or vasodilator stress (
      • Peltier M.
      • Vancraeynest D.
      • Pasquet A.
      • Ay T.
      • Roelants V.
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      • Melin J.A.
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      Assessment of the physiologic significance of coronary disease with dipyridamole real-time myocardial contrast echocardiography. Comparison with technetium-99 m sestamibi single-photon emission computed tomography and quantitative coronary angiography.
      ;
      • Vogel R.
      • Indermuhle A.
      • Reinhardt J.
      • Meier P.
      • Siegrist P.T.
      • Namdar M.
      • Kaufmann P.A.
      • Seiler C.
      The quantification of absolute myocardial perfusion in humans by contrast echocardiography: Algorithm and validation.
      ;
      • Hacker M.
      • Hoyer H.X.
      • Uebleis C.
      • Ueberfuhr P.
      • Foerster S.
      • La Fougere C.
      • Stempfle H.U.
      Quantitative assessment of cardiac allograft vasculopathy by real-time myocardial contrast echocardiography: A comparison with conventional echocardiographic analyses and [Tc99 m]-sestamibi SPECT.
      ;
      • Hayat S.A.
      • Dwivedi G.
      • Jacobsen A.
      • Lim T.K.
      • Kinsey C.
      • Senior R.
      Effects of left bundle-branch block on cardiac structure, function, perfusion, and perfusion reserve: Implications for myocardial contrast echocardiography versus radionuclide perfusion imaging for the detection of coronary artery disease.
      ;
      • Lipiec P.
      • Wejner-Mik P.
      • Krzeminska-Pakula M.
      • Kusmierek J.
      • Plachcinska A.
      • Szuminski R.
      • Peruga J.Z.
      • Kasprzak J.D.
      Accelerated stress real-time myocardial contrast echocardiography for the detection of coronary artery disease: Comparison with 99 mTc single photon emission computed tomography.
      ;
      • Xie F.
      • Dodla S.
      • O'Leary E.
      • Porter T.R.
      Detection of subendocardial ischemia in the left anterior descending coronary artery territory with real-time myocardial contrast echocardiography during dobutamine stress echocardiography.
      ;
      • Abdelmoneim S.S.
      • Dhoble A.
      • Bernier M.
      • Erwin P.J.
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      • Senior R.
      • Moir S.
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      • Dawson D.
      • Vogel R.
      • Wei K.
      • West C.P.
      • Montori V.M.
      • Pellikka P.A.
      • Abdel-Kader S.S.
      • Mulvagh S.L.
      Quantitative myocardial contrast echocardiography during pharmacological stress for diagnosis of coronary artery disease: A systematic review and meta-analysis of diagnostic accuracy studies.
      ;
      • Abdelmoneim S.S.
      • Dhoble A.
      • Bernier M.
      • Moir S.
      • Hagen M.E.
      • Ness S.A.
      • Abdel-Kader S.S.
      • Pellikka P.A.
      • Mulvagh S.L.
      Absolute myocardial blood flow determination using real-time myocardial contrast echocardiography during adenosine stress: Comparison with single-photon emission computed tomography.
      ;
      • Dolan M.S.
      • Gala S.S.
      • Dodla S.
      • Abdelmoneim S.S.
      • Xie F.
      • Cloutier D.
      • Bierig M.
      • Mulvagh S.L.
      • Porter T.R.
      • Labovitz A.J.
      Safety and efficacy of commercially available ultrasound contrast agents for rest and stress echocardiography a multicenter experience.
      ;
      • Miszalski-Jamka T.
      • Kuntz-Hehner S.
      • Schmidt H.
      • Peter D.
      • Miszalski-Jamka K.
      • Hammerstingl C.
      • Tiemann K.
      • Ghanem A.
      • Troatz C.
      • Pasowicz M.
      • Luderitz B.
      • Omran H.
      Myocardial contrast echocardiography enhances long-term prognostic value of supine bicycle stress two-dimensional echocardiography.
      ;
      • Arnold J.R.
      • Karamitsos T.D.
      • Pegg T.J.
      • Francis J.M.
      • Olszewski R.
      • Searle N.
      • Senior R.
      • Neubauer S.
      • Becher H.
      • Selvanayagam J.B.
      Adenosine stress myocardial contrast echocardiography for the detection of coronary artery disease: A comparison with coronary angiography and cardiac magnetic resonance.
      ;
      • Gaibazzi N.
      • Rigo F.
      • Squeri A.
      • Ugo F.
      • Reverberi C.
      Incremental value of contrast myocardial perfusion to detect intermediate versus severe coronary artery stenosis during stress-echocardiography.
      ;
      • Porter T.R.
      • Adolphson M.
      • High R.R.
      • Smith L.M.
      • Olson J.
      • Erdkamp M.
      • Xie F.
      • O'Leary E.
      • Wong B.F.
      • Eifert-Rain S.
      • Hagen M.E.
      • Abdelmoneim S.S.
      • Mulvagh S.L.
      Rapid detection of coronary artery stenoses with real-time perfusion echocardiography during regadenoson stress.
      ;
      • Gaibazzi N.
      • Reverberi C.
      • Lorenzoni V.
      • Molinaro S.
      • Porter T.R.
      Prognostic value of high-dose dipyridamole stress myocardial contrast perfusion echocardiography.
      ;
      • Porter T.R.
      • Smith L.M.
      • Wu J.
      • Thomas D.
      • Haas J.T.
      • Mathers D.H.
      • Williams E.
      • Olson J.
      • Nalty K.
      • Hess R.
      • Therrien S.
      • Xie F.
      Patient outcome following 2 different stress imaging approaches: A prospective randomized comparison.
      ).
      Fig 3
      Fig. 3Inducible subendocardial microvascular perfusion defect (arrows) detected with real-time VLMI imaging and a continuous ultrasound contrast infusion in a patient during stress echocardiography. a shows resting myocardial contrast replenishment, which is normal, while b indicates a subendocardial inferolateral defect (arrows) and transmural apical defect (arrowheads) during stress imaging.
      VLMI = very low mechanical index.
      Fig 4
      Fig. 4Persistent anterior and apical microvascular perfusion defect (arrows) after successful percutaneous recanalization of the left anterior descending.
      Fig 5
      Fig. 5Another example from a patient with an acute lateral wall myocardial infarction who underwent successful epicardial recanalization of a circumflex marginal artery that was 100% occluded. After percutaneous coronary intervention, there was normal epicardial flow (termed TIMI Grade III) in the circumflex, but persistent basal to mid-anterolateral microvascular defect on resting very low mechanical index imaging (arrows).
      Table 2Different very low mechanical index (VLMI) imaging techniques
      VLMI Imaging ModalityContrast Detection Pulse Sequence SchemeAdvantagesDisadvantagesComments
      Power modulationAlternating amplitudeIncreased contrast and significantly less far field attenuationLower resolution, reduced signal to noise ratioDetects fundamental non-linear activity
      Contrast pulse sequencingAlternating amplitude and phase modulationHigh sensitivity, minimal attenuationHigh sensitivity to microbubbles and reduced dynamic range may make it less sensitive for detecting myocardial blood flow abnormalitiesDetects fundamental and harmonic non-linear activity
      Phase inversionAlternating phaseGood signal to noise ratioFar field attenuation.Detects even order harmonics

      Detection of Myocardial Ischemia

      In the setting of dobutamine stress echocardiography, perfusion analysis has improved coronary artery disease (CAD) detection compared with wall motion analysis alone (
      • Xie F.
      • Dodla S.
      • O'Leary E.
      • Porter T.R.
      Detection of subendocardial ischemia in the left anterior descending coronary artery territory with real-time myocardial contrast echocardiography during dobutamine stress echocardiography.
      ;
      • Porter T.R.
      • Smith L.M.
      • Wu J.
      • Thomas D.
      • Haas J.T.
      • Mathers D.H.
      • Williams E.
      • Olson J.
      • Nalty K.
      • Hess R.
      • Therrien S.
      • Xie F.
      Patient outcome following 2 different stress imaging approaches: A prospective randomized comparison.
      ). The improvement appears to be related to the ischemic cascade, where perfusion abnormalities have been shown to occur before wall motion abnormalities during demand ischemia (
      • Leong-Poi H.
      • Rim S.J.
      • Le D.E.
      • Fisher N.G.
      • Wei K.
      • Kaul S.
      Perfusion versus function: The ischemic cascade in demand ischemia: Implications of single-vessel versus multivessel stenosis.
      ). The 20–30 Hz frame rates with VLMI imaging allows for simultaneous analysis of regional wall motion (RWM) and microvascular perfusion (MVP). Perfusion echocardiography, compared with radionuclide imaging or positron emission tomography (PET), has higher resolution and permits the detection of subendocardial ischemia (Fig. 3), which is not possible with radionuclide techniques or PET (
      • Xie F.
      • Dodla S.
      • O'Leary E.
      • Porter T.R.
      Detection of subendocardial ischemia in the left anterior descending coronary artery territory with real-time myocardial contrast echocardiography during dobutamine stress echocardiography.
      ;
      • Porter T.R.
      • Smith L.M.
      • Wu J.
      • Thomas D.
      • Haas J.T.
      • Mathers D.H.
      • Williams E.
      • Olson J.
      • Nalty K.
      • Hess R.
      • Therrien S.
      • Xie F.
      Patient outcome following 2 different stress imaging approaches: A prospective randomized comparison.
      ). The higher resolution of VLMI imaging also may be useful in patient populations with resting non-ischemic wall motion abnormalities such as ventricular-paced rhythms or left bundle branch block (LBBB) (
      • Hayat S.A.
      • Dwivedi G.
      • Jacobsen A.
      • Lim T.K.
      • Kinsey C.
      • Senior R.
      Effects of left bundle-branch block on cardiac structure, function, perfusion, and perfusion reserve: Implications for myocardial contrast echocardiography versus radionuclide perfusion imaging for the detection of coronary artery disease.
      ). Adding perfusion information to RWM analysis has resulted in better defining the extent of CAD that exists (Fig. 6) and is better than RWM analysis alone in identifying those at risk for subsequent cardiac events (
      • Leong-Poi H.
      • Rim S.J.
      • Le D.E.
      • Fisher N.G.
      • Wei K.
      • Kaul S.
      Perfusion versus function: The ischemic cascade in demand ischemia: Implications of single-vessel versus multivessel stenosis.
      ;
      • Porter T.R.
      • Smith L.M.
      • Wu J.
      • Thomas D.
      • Haas J.T.
      • Mathers D.H.
      • Williams E.
      • Olson J.
      • Nalty K.
      • Hess R.
      • Therrien S.
      • Xie F.
      Patient outcome following 2 different stress imaging approaches: A prospective randomized comparison.
      ).
      Fig 6
      Fig. 6Dobutamine stress imaging in a patient undergoing a stem cell transplantation evaluation for multiple myeloma. Observe on the apical two-chamber view that there is no resting myocardial perfusion defect (a), but a moderate sized mid and distal anterior perfusion defect in the absence of a wall thickening abnormality during dobutamine stress (b, arrows).
      Perfusion abnormalities during demand stress have been correlated with fractional flow reserve (FFR) measurements using invasive hemodynamics in patients with intermediate angiographic stenosis between 50% and 80% in diameter (
      • Xie F.
      • Dodla S.
      • O'Leary E.
      • Porter T.R.
      Detection of subendocardial ischemia in the left anterior descending coronary artery territory with real-time myocardial contrast echocardiography during dobutamine stress echocardiography.
      ). Although demand stress has excellent sensitivity for detecting either abnormal FFR or resting pressure gradient across the stenosis, demand MVP is frequently abnormal in patients with intermediate stenoses that have normal FFR. In this setting, invasive hemodynamic measurements of hyperemic microvascular resistance have been found to be abnormal and correlate more closely with abnormal MVP (
      • Leong-Poi H.
      • Rim S.J.
      • Le D.E.
      • Fisher N.G.
      • Wei K.
      • Kaul S.
      Perfusion versus function: The ischemic cascade in demand ischemia: Implications of single-vessel versus multivessel stenosis.
      ). Since perfusion echocardiography measures both capillary blood velocity and blood volume, stress-induced abnormalities may exist before detection of significant hyperemic pressure changes across a stenosis in the 50%–80% range. Abnormal MVP may even exist in the absence of a significant epicardial stenosis. When these abnormalities are found in patients, their clinical event rate (death, non-fatal myocardial infarction) appears to be as poor as those with abnormal MVP and significant epicardial disease (
      • Kutty S.
      • Bisselou Moukagna K.S.
      • Craft M.
      • Shostrom V.
      • Xie F.
      • Porter T.R.
      Clinical outcome of patients with inducible capillary blood flow abnormalities during demand stress in the presence or absence of angiographic coronary disease.
      ).

      Perfusion Imaging During Vasodilator Stress

      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 owing to the lower heart rate (often not exceeding 100 beats per min) and less translational cardiac movement (
      • Lipiec P.
      • Wejner-Mik P.
      • Krzeminska-Pakula M.
      • Kusmierek J.
      • Plachcinska A.
      • Szuminski R.
      • Peruga J.Z.
      • Kasprzak J.D.
      Accelerated stress real-time myocardial contrast echocardiography for the detection of coronary artery disease: Comparison with 99 mTc single photon emission computed tomography.
      ;
      • Miszalski-Jamka T.
      • Kuntz-Hehner S.
      • Schmidt H.
      • Peter D.
      • Miszalski-Jamka K.
      • Hammerstingl C.
      • Tiemann K.
      • Ghanem A.
      • Troatz C.
      • Pasowicz M.
      • Luderitz B.
      • Omran H.
      Myocardial contrast echocardiography enhances long-term prognostic value of supine bicycle stress two-dimensional echocardiography.
      ;
      • Arnold J.R.
      • Karamitsos T.D.
      • Pegg T.J.
      • Francis J.M.
      • Olszewski R.
      • Searle N.
      • Senior R.
      • Neubauer S.
      • Becher H.
      • Selvanayagam J.B.
      Adenosine stress myocardial contrast echocardiography for the detection of coronary artery disease: A comparison with coronary angiography and cardiac magnetic resonance.
      ). Adenosine and dipyridamole are the most commonly used vasodilators for perfusion imaging. Both agents act non-selectively directly or indirectly to activate all four adenosine receptor subtypes (A1, A2 A, A2 B and A3), resulting in transient symptoms. Regadenoson is a potent selective A2 A agonist, administered as a 400 µg intravenous bolus, with rapid onset of action (within 30 seconds) and adequate duration of action to allow sufficient time for VLMI image acquisition (
      • Porter T.R.
      • Adolphson M.
      • High R.R.
      • Smith L.M.
      • Olson J.
      • Erdkamp M.
      • Xie F.
      • O'Leary E.
      • Wong B.F.
      • Eifert-Rain S.
      • Hagen M.E.
      • Abdelmoneim S.S.
      • Mulvagh S.L.
      Rapid detection of coronary artery stenoses with real-time perfusion echocardiography during regadenoson stress.
      ). Large multi-center trials comparing VLMI imaging with single-photon emission computed tomography (SPECT) imaging using dipyridamole for the detection of CAD have been performed (
      • Senior R.
      • Moreo A.
      • Gaibazzi N.
      • Agati L.
      • Tiemann K.
      • Shivalkar B.
      • von Bardeleben S.
      • Galiuto L.
      • Lardoux H.
      • Trocino G.
      • Carrio I.
      • Le Guludec D.
      • Sambuceti G.
      • Becher H.
      • Colonna P.
      • Ten Cate F.
      • Bramucci E.
      • Cohen A.
      • Bezante G.
      • Aggeli C.
      • Kasprzak J.D.
      Comparison of sulfur hexafluoride microbubble (SonoVue)-enhanced myocardial contrast echocardiography with gated single-photon emission computed tomography for detection of significant coronary artery disease: A large European multicenter study.
      ). When using coronary angiography as a reference standard, the sensitivity of myocardial contrast echocardiography (MCE) in this setting has been shown to be superior to SPECT. The basis of superior sensitivity appears to be the better spatial resolution of VLMI perfusion versus SPECT and that vasodilator SPECT assesses only capillary blood volume while MCE detects both capillary blood volume and capillary velocity, the latter being a more sensitive marker of CAD (
      • Wei K.
      • Le E.
      • Bin J.P.
      • Coggins M.
      • Jayawera A.R.
      • Kaul S.
      Mechanism of reversible (99 m)Tc-sestamibi perfusion defects during pharmacologically induced vasodilatation.
      ). In specific patient populations with resting non-ischemic wall motion abnormalities, such as LBBB or paced rhythm, real-time MCE has permitted improved detection of ischemia compared with radionuclide imaging, and thus may be particularly useful in this setting (
      • Hayat S.A.
      • Dwivedi G.
      • Jacobsen A.
      • Lim T.K.
      • Kinsey C.
      • Senior R.
      Effects of left bundle-branch block on cardiac structure, function, perfusion, and perfusion reserve: Implications for myocardial contrast echocardiography versus radionuclide perfusion imaging for the detection of coronary artery disease.
      ).

      VLMI Perfusion Imaging to Predict Outcomes

      Clinical outcome studies have shown that hard cardiac events (death or myocardial infarction) at 2 y could also be better predicted with VLMI perfusion and RWM analysis more than RWM assessment alone (
      • Porter T.R.
      • Smith L.M.
      • Wu J.
      • Thomas D.
      • Haas J.T.
      • Mathers D.H.
      • Williams E.
      • Olson J.
      • Nalty K.
      • Hess R.
      • Therrien S.
      • Xie F.
      Patient outcome following 2 different stress imaging approaches: A prospective randomized comparison.
      ). In each of these settings, delayed replenishment of contrast during slow bolus or continuous infusion of UCAs was seen in a significant percentage of patients in the absence of RWM abnormalities and appeared to have independent prognostic value for prediction of subsequent death and non-fatal myocardial infarction. Data of 5-y follow-up in over 1300 patients after high-dose dipyridamole perfusion stress echocardiography have shown that incremental prognostic information is obtained when combining myocardial perfusion with RWM analysis (
      • Gaibazzi N.
      • Porter T.
      • Lorenzoni V.
      • Pontone G.
      • De Santis D.
      • De Rosa A.
      • Guaricci A.I.
      Effect of coronary revascularization on the prognostic value of stress myocardial contrast wall motion and perfusion imaging.
      ).
      Detection of resting myocardial perfusion defects in patients with chest pain and non-diagnostic electrocardiograms (Fig. 7) has been shown to add significant predictive value to clinical, electrocardiogram and biomarker data in predicting short- and longer-term outcome (
      • Wei K.
      • Peters D.
      • Belcik T.
      • Kalvaitis S.
      • Womak L.
      • Rinkevich D.
      • Tong K.L.
      • Horton K.
      • Kaul S.
      A predictive instrument using contrast echocardiography in patients presenting to the emergency department with chest pain and without ST-segment elevation.
      ).
      Fig 7
      Fig. 7An example of a resting microvascular perfusion abnormality detected with real-time very low mechanical index imaging in the inferolateral and apical segments (arrows) in a patient being evaluated for chest pain and a non-diagnostic electrocardiogram. The unenhanced image is displayed on the left.

      Ultrasound Contrast Agents: Safety and Efficacy in Clinical Studies Examining On- and Off-Label Indicationst

      UCAs are safely and routinely used throughout the world to enhance ultrasound imaging of the heart, carotid arteries, liver, kidney, bowel and other organ systems throughout the body. Sometimes also known in echocardiography as ultrasound-enhancing agents, UCAs improve the clarity of conventional ultrasound images and the accuracy, reliability and utility of ultrasound diagnoses in real time and without ionizing radiation. When administered during an echocardiogram, UCAs provide high-resolution images that can dramatically improve the detection of cardiovascular abnormalities and stratify risk of heart attack or stroke. UCAs also produce superb real-time images of vascularity that allow for characterization of tumors and monitoring of their growth patterns and treatment efficacy. Consequently, UCAs often alter therapy, positively affect outcomes and save lives. One recent study showed a 28% reduction in mortality in critically ill cardiac patients compared with propensity-matched populations (
      • Main M.L.
      • Hibberd M.G.
      • Ryan A.
      • Lowe T.J.
      • Miller P.
      • Bhat G.
      Acute mortality in critically ill patients undergoing echocardiography with or without an ultrasound contrast agent.
      ).
      UCAs also reduce the need for redundant or alternative testing, which in turn can avoid exposing patients to ionizing radiation, invasive catheterization, sedation, anesthesia and other contrast agents that may increase the risk of kidney damage. In addition, by providing real-time diagnostic information, UCAs also can speed up the time to diagnosis and avoid risks associated with delayed access to appropriate therapy. And by reducing the need for more expensive diagnostic imaging, UCAs can lower overall imaging costs, improve hospital workflows and provide a more efficient and comfortable patient experience (
      • Kurt M.
      • Shaikh K.A.
      • Peterson L.
      • Kurrelmeyer K.M.
      • Shah G.
      • Nagueh S.F.
      • Fromm R.
      • Quinones M.A.
      • Zoghbi W.A.
      Impact of contrast echocardiography on evaluation of ventricular function and clinical management in a large prospective cohort.
      ).
      In the United States, UCAs were first approved by the U.S. Food and Drug Administration (FDA) for cardiac applications in 1994, but it was not until 2016 that the FDA extended their use to the liver and pediatric indications. However, clinicians are permitted to use medical products “off label” for additional unapproved indications where medically appropriate, and UCAs are increasingly used to image the kidney, bowel and carotid arteries, etc. On-label and off-label indications are supported by professional society guidelines, accreditation standards and newer organ-agnostic billing codes that are used to determine payment for medical procedures in the United States.
      Novel, exciting therapeutic uses of UCAs also are in development. UCAs are now being used clinically for sonothrombolysis in the aftermath of a myocardial infarction, with favorable results (
      • Mathias Jr, W.T.J.
      • Tavares B.G.
      • Fava A.M.
      • Aguiar M.O.D.
      • Borges B.C.
      • Oliveira Jr, M.T.
      • Soeiro A.
      • Nicolau J.C.
      • Ribeiro H.B.
      • Pochiang H.
      • Sbano J.C.N.
      • Morad A.
      • Goldsweig A.
      • Rochitte C.E.
      • Lopez B.B.C.
      • Ramirez J.A.F.
      • Filho R.K.
      • Porter T.R.
      Microvascular recovery with ultrasound in acute myocardial infarction (MRUSMI) investigators. Sonothrombolysis in ST segment elevation myocardial infarction treated with primary percutaneous coronary intervention.
      ) In addition, pre-clinical studies are using UCAs and sonoporation to deliver drug and gene therapies and promise to provide a safe alternative to the use of viruses for drug and gene therapy.
      UCAs are among the safest diagnostic imaging products available, and the risks associated with UCA use are exceedingly rare and generally mild. Idiosyncratic anaphylactoid reactions associated with UCAs occur in ∼1:10,000 patients. According to a meta-analysis of UCA use in 110,500 patients, serious allergic reactions may occur in 0.009% of patients and anaphylactoid reactions may occur in 0.004% of patients. These reactions generally resolve spontaneously and may be secondary to complement activation related pseudo allergy (CARPA), which in turn may be more common with bolus UCA administration than with continuous administration. Mild to moderate CARPA reactions may include sneezing, tingling sensation, urticaria or pruritis, whereas more severe CARPA reactions may include wheezing, angioedema, cyanosis or anaphylactic shock. As a precaution, clinicians may keep an allergy kit with an adrenaline injection nearby. Further, although rare, back or flank pain also may be experienced with lipid shell UCAs (
      • Muskula P.R.
      • Main M.L.
      Safety with echocardiographic contrast agents.
      ).
      Thirteen y into the use of UCAs in the United States, as patients were increasingly benefitting from their safe and effective diagnostic application, the FDA mandated a “black box” on UCA package inserts along with other label modifications. A “black box” is intended to indicate the most severe level of risk associated with a medical product. The FDA action was based on spontaneous reports of four deaths and 190 severe reactions that were temporally associated with, but not clearly caused by, UCA administration. However, independent reviewers subsequently concluded that the four deaths were likely caused by the progression of the patients’ underlying conditions, not the temporal administration of a UCA (
      • Muskula P.R.
      • Main M.L.
      Safety with echocardiographic contrast agents.
      ).
      Because of the FDA's action, researchers proceeded to conduct numerous large safety studies that evaluated UCA use in out-patients, hospitalized patients, patients undergoing stress echocardiography and patients with pulmonary hypertension. These studies created a substantial evidence-based record demonstrating a strong safety profile for UCAs in diverse clinical settings. The seminal 2017 paper by
      • Muskula P.R.
      • Main M.L.
      Safety with echocardiographic contrast agents.
      provides a comprehensive, state-of-the-art review and analysis of the clinical studies demonstrating the safety of UCAs.
      The “black box” also motivated practitioners to launch the International Contrast Ultrasound Society (ICUS), a grassroots not-for-profit medical society exclusively focusing on advancing the safe and appropriate use of UCAs where medically indicated to improve patient care worldwide (www.ICUS-society.org). Since its founding in 2008, ICUS has become a strong, global and inter-disciplinary voice for the contrast-enhanced ultrasound (CEUS) field. ICUS members in 60 countries include physicians, sonographers, nurses, scientists and other ultrasound professionals in the fields of cardiology, radiology, pediatrics, hepatology, vascular imaging, internal medicine, gastro-intestinal medicine, emergency medicine and intensive care, etc. ICUS now offers a global platform for CEUS communication, education and advocacy. To encourage wider access to the latest CEUS information, ICUS offers free membership, free website access, free weekly CEUS updates (available in English and Mandarin) and low-cost continuing medical education programming.
      ICUS and other stakeholders have periodically advocated for the rollback of certain mandated warnings and contraindications based on the growing body of favorable safety studies. The FDA has responded by thoughtfully reviewing the developing science and narrowing the warning language inside the “black box,” as well as making other label modifications. As of the date of this writing, the boxed warnings, which are substantially similar for all three FDA-approved UCAs, state that (i) serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or after UCA administration; (ii) most serious reactions occur within 30 min of administration; (iii) all patients should be assessed for the presence of any condition that precludes administration; and (iv) resuscitation equipment and trained personnel should always be readily available.
      Most recently, ICUS filed its second Citizen Petition with the FDA, seeking removal of the “black box” based on current scientific literature and clinical experiences. The ICUS Citizen Petition concluded that, although certain warning language may be appropriate in the “warnings and precautions” section of the product labels, the growing body of scientific evidence now shows that UCAs do not present the very highest level of risk associated with a “black box.” The Petition also concluded that the “boxed warnings on UCAs deter patient access to safe, real time diagnostic information and therefore have serious deleterious implications on the health of the American public.” Letters supporting the ICUS Citizen Petition have been submitted to the FDA by other ultrasound professional societies and CEUS experts. The Citizen Petition remains pending as of the date of this writing.
      The safety and efficacy profile of UCAs is well established by a growing body of scientific literature as well as extensive clinical experience globally. UCAs can change patient outcomes and save lives, while also reducing redundant or alternative testing, lowering overall imaging costs and improving hospital workflows and patient experiences. Healthcare professionals must remain informed of the risks associated with any medical procedure including CEUS and prepare accordingly (Table 3).
      Table 3Selection of ultrasound contrast agents study on safety (28)
      AuthorPublication dateStudy designECAPatients (N)Controls (N)Rest/stressOutcome
      Aggeli et al.2008ProspectiveSonovue5250NAStressNo deaths or mechanical index
      Main et al.2008RetrospectiveDefinity582544242712RestNo increased mortality in ECA patients
      Wei et al.2008RetrospectiveDefinity or Optison78383NABothSevere allergic reactions in 0.01% and anaphylactic reactions in 0.006%
      Dolan et al.2009RetrospectiveDefinity or Optison4240823812BothNo increased mortality in ECA patients
      Exuzides et al.2010RetrospectiveOptison290011600RestNo increased mortality in ECA patients
      Goldberg et al.2012RetrospectiveDefinity251894187BothNo increased mortality in ECA patients
      Wei et al.2014ProspectiveOptison1039NABothNo deaths or serious adverse events
      Definity is marketed as Luminity in Europe.
      ECA = echocardiography contrast agent; NA = not applicable.

      Sonothrombolysis

      The potential for intermittent high MI impulses from a diagnostic transducer to dissolve intravascular thrombi without the need for fibrinolytic therapy or anticoagulation was first demonstrated in a canine model of arteriovenous graft thrombosis, where intermittent high MI impulses (all <1.9 MI) were applied when low MI imaging detected microbubbles within the graft (
      • Xie F.
      • Lof J.
      • Everbach C.
      • He A.
      • Bennett R.M.
      • Matsunaga T.
      • Johanning J.
      • Porter T.R.
      Treatment of acute intravascular thrombi with diagnostic ultrasound and intravenous microbubbles.
      ). The high MI impulses with short (<5 usec) pulse duration induce transient inertial cavitation of microbubbles channeling through small micropores within the thrombus, resulting in fluid jets, which have been shown to mechanically erode the thrombus (
      • Chen X.
      • Leeman J.E.
      • Wang J.
      • Pacella J.J.
      • Villanueva F.S.
      New insights into mechanisms of sonothrombolysis using ultra-high-speed imaging.
      ). Subsequent pre-clinical studies examined the efficacy of diagnostic high MI impulses in restoring microvascular and epicardial blood flow in porcine models of acute ST elevation myocardial infarction (STEMI) (
      • Xie F.
      • Gao S.
      • Wu J.
      • Lof J.
      • Radio S.
      • Vignon F.
      • Shi W.
      • Powers J.
      • Unger E.
      • Everbach E.C.
      • Liu J.
      • Porter T.R.
      Diagnostic ultrasound induced inertial cavitation to non-invasively restore coronary and microvascular flow in acute myocardial infarction.
      ). Since epicardial vessels are not easily visualized with diagnostic ultrasound (DUS), these studies used VLMI imaging of the microvasculature to guide the timing of the high MI impulses. It was demonstrated that intermittent high MI impulses from a transthoracic DUS transducer increased epicardial recanalization rates from 36%, seen with a half dose of tissue plasminogen activator (tPA) alone, to 83%, with DUS high MI impulses and microbubbles combined with a half dose of tPA. Furthermore, ST segment resolution was seen with DUS high MI impulses even when epicardial recanalization was not achieved, indicating vasoactive mediators were playing a role in restoring microvascular flow even in the absence of upstream large vessel flow. Subsequent small animal studies with ischemic peripheral vessel occlusion confirmed that high MI DUS impulses induce purinergic-mediated nitric oxide release, resulting in restoration of microvascular flow, even in the presence of a persistent upstream vessel occlusion (
      • Belcik J.T.
      • Davidson B.P.
      • Xie A.
      • Wu M.D.
      • Yadava M.
      • Qi Y.
      • Liang S.
      • Chon C.R.
      • Ammi A.Y.
      • Field J.
      • Harmann L.
      • Chilian W.M.
      • Linden J.
      • Lindner J.R.
      Augmentation of muscle blood flow by ultrasound cavitation is mediated by ATP and purinergic signaling.
      ). These pre-clinical observations prompted the first randomized controlled trial in acute STEMI patients, which demonstrated that the guided high MI short pulse duration diagnostic impulses improved early epicardial recanalization rates and reduced myocardial infarction size (
      • Mathias Jr, W.T.J.
      • Tavares B.G.
      • Fava A.M.
      • Aguiar M.O.D.
      • Borges B.C.
      • Oliveira Jr, M.T.
      • Soeiro A.
      • Nicolau J.C.
      • Ribeiro H.B.
      • Pochiang H.
      • Sbano J.C.N.
      • Morad A.
      • Goldsweig A.
      • Rochitte C.E.
      • Lopez B.B.C.
      • Ramirez J.A.F.
      • Filho R.K.
      • Porter T.R.
      Microvascular recovery with ultrasound in acute myocardial infarction (MRUSMI) investigators. Sonothrombolysis in ST segment elevation myocardial infarction treated with primary percutaneous coronary intervention.
      ). All studies were done with commercially available DUS scanners and UCAs and indicate the potential for this technique to restore myocardial function within the risk area. Ongoing studies are now determining whether this same sonothrombolysis technique can reduce the frequency of microvascular obstruction that persists after successful epicardial recanalization in acute ST segment elevation myocardial infarction (Fig. 8).
      Fig 8
      Fig. 8Example of a resting distal septal and apical microvascular perfusion defect (a, arrows), which persisted despite successful recanalization of the left anterior descending in an acute myocardial infarction patient. However, after 20 min of intermittent high mechanical index (MI) impulses applied to the apical four, two and three chamber views, the microvascular defect resolved (b).

      Application in Acute Patients

      Most patients presenting to the emergency department (ED) with chest pain do not have significant ST segment depression or elevation, and many patients with acute myocardial infarction do not describe typical angina-quality chest discomfort. Additionally, conventional cardiac biomarker assessment has low sensitivity for detection of myocardial necrosis in the early hours of acute myocardial infarction. Given these limitations, echocardiographic assessment of wall thickening and MVP have been shown to provide rapid risk stratification in patients presenting to the ED with suspected myocardial ischemia (
      • Wyrick J.J.
      • Kalvaitis S.
      • McConnell K.J.
      • Rinkevich D.
      • Kaul S.
      • Wei K.
      Cost-efficiency of myocardial contrast echocardiography in patients presenting to the emergency department with chest pain of suspected cardiac origin and a nondiagnostic electrocardiogram.
      ;
      • Wei K.
      • Peters D.
      • Belcik T.
      • Kalvaitis S.
      • Womak L.
      • Rinkevich D.
      • Tong K.L.
      • Horton K.
      • Kaul S.
      A predictive instrument using contrast echocardiography in patients presenting to the emergency department with chest pain and without ST-segment elevation.
      ). Wei et al. examined MVP and wall thickening during a contrast infusion in more than 1000 patients with a chest pain presentation in the ED. A risk model was developed that incorporated electrocardiogram, RWM and resting MCE, which was subsequently validated in 720 patients. Abnormal RWM with normal MCE and abnormal RWM with abnormal MCE added significant predictive value to electrocardiogram abnormalities in predicting non-fatal myocardial infarction or cardiac death (
      • Wei K.
      • Peters D.
      • Belcik T.
      • Kalvaitis S.
      • Womak L.
      • Rinkevich D.
      • Tong K.L.
      • Horton K.
      • Kaul S.
      A predictive instrument using contrast echocardiography in patients presenting to the emergency department with chest pain and without ST-segment elevation.
      ). Using the predictive value of normal MCE and RWM information obtained from contrast echocardiography in these patients could reduce overall hospital admission rates by 45% (
      • Wyrick J.J.
      • Kalvaitis S.
      • McConnell K.J.
      • Rinkevich D.
      • Kaul S.
      • Wei K.
      Cost-efficiency of myocardial contrast echocardiography in patients presenting to the emergency department with chest pain of suspected cardiac origin and a nondiagnostic electrocardiogram.
      ).
      The assessment of MCE has also been used after the emergent management of ST segment myocardial infarction, or STEMI (
      • Galiuto L.
      • Garramone B.
      • Scara A.
      • Rebuzzi A.G.
      • Crea F.
      • La Torre G.
      • Funaro S.
      • Madonna M.
      • Fedele F.
      • Agati L.
      • Investigators A.
      The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodeling: Results of the multicenter AMICI study.
      ;
      • Aggarwal S.
      • Xie F.
      • High R.
      • Pavlides G.
      • Porter T.R.
      Prevalence and predictive value of microvascular flow abnormalities after successful contemporary percutaneous coronary intervention in acute ST-segment elevation myocardial infarction.
      ). Even after successful early recanalization of the infarct vessel, a persistent resting MVP defect within the infarct territory has been shown to provide independent predictive value with regard to adverse LV remodeling and recurrent cardiac events (death and recurrent infarction) after STEMI (
      • Galiuto L.
      • Garramone B.
      • Scara A.
      • Rebuzzi A.G.
      • Crea F.
      • La Torre G.
      • Funaro S.
      • Madonna M.
      • Fedele F.
      • Agati L.
      • Investigators A.
      The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodeling: Results of the multicenter AMICI study.
      ). VLMI imaging with UCAs in this setting again permits the simultaneous assessment of two prognostically important measures before hospital discharge in post-STEMI patients: the assessment of LV systolic function, and degree of microvascular obstruction. Although angiographic recanalization with normalized epicardial flow has been achieved with contemporary percutaneous interventional techniques, microvascular obstruction may still be present in a significant percentage of patients, especially in patients with infarction involving the left anterior descending territory (Fig. 4). Persistent abnormalities in microvascular flow in these patients increases the risk for adverse left ventricular remodeling, heart failure, re-infarction and death (
      • Aggarwal S.
      • Xie F.
      • High R.
      • Pavlides G.
      • Porter T.R.
      Prevalence and predictive value of microvascular flow abnormalities after successful contemporary percutaneous coronary intervention in acute ST-segment elevation myocardial infarction.
      ).

      Conclusion

      Current research provides good evidence that myocardial perfusion echocardiography improves comprehensive echocardiographic evaluations of ischemic heart disease. The approval of regulatory authorities and the availability of quantitative operator-independent analysis software will hopefully prompt physicians and sonographers to implement myocardial perfusion echocardiography into the daily workflow of echo laboratories. New diagnostic and therapeutic applications will result in improved patient care, especially in the area of sonothrombolysis, where preliminary data have already shown its utilization in how STEMI can improve LV systolic function and reduce the need for implantable defibrillators at 6 mo follow-up (
      • Mathias Jr, W.T.J.
      • Tavares B.G.
      • Fava A.M.
      • Aguiar M.O.D.
      • Borges B.C.
      • Oliveira Jr, M.T.
      • Soeiro A.
      • Nicolau J.C.
      • Ribeiro H.B.
      • Pochiang H.
      • Sbano J.C.N.
      • Morad A.
      • Goldsweig A.
      • Rochitte C.E.
      • Lopez B.B.C.
      • Ramirez J.A.F.
      • Filho R.K.
      • Porter T.R.
      Microvascular recovery with ultrasound in acute myocardial infarction (MRUSMI) investigators. Sonothrombolysis in ST segment elevation myocardial infarction treated with primary percutaneous coronary intervention.
      ).

      Conflict of interest disclosure

      The authors declare no competing interests.

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