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MINERVA CARDIOANGIOL 2011;59:519-28

Current applications of contrast echocardiography

IN C ER O V P A Y R M IG E H DI T C ® A

G. NUCIFORA, F. F. FALETRA

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Transthoracic echocardiography is a practical, widely available non-invasive imaging technique examining cardiac structure and function at rest and during stress. However, diagnostically useful images are not provided in a non-negligible proportion of patients, mainly because of obesity and lung disease. The use of echo-contrast agents (microbubbles consisting of high molecular weight gas encapsulated in a outer shell which have ultrasound characteristics distinctly different from those of the surrounding blood cells and heart tissue) solves these issues, providing cardiac chamber opacification and improving endocardial border definition, consequently allowing a more accurate quantification of left ventricular function. Besides improving the assessment of left ventricular function, echo-contrast agents may be used also to assess the myocardial perfusion at the capillary level, providing useful information about myocardial blood flow. Aim of the present paper is to provide an overview of the main clinical applications of contrast echocardiography, i.e. left ventricular opacification and myocardial contrast echocardiography. Key words: Echocardiography - Heart ventricles Myocardial perfusion imaging.

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im of the present paper wasto provide an overview of the main clinical applications of contrast echocardiography, i.e., left ventricular opacification and myocardial contrast echocardiography (Table I).

Corresponding author: G. Nucifora, MD, Division of Cardiology, Fondazione Cardiocentro Ticino, via Tesserete 48, 6900 Lugano, Switzerland. E-mail: [email protected]

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Department of Cardiology Fondazione Cardiocentro Ticino Lugano, Switzerland

Left ventricular opacification

Contrast echocardiography has been extensively demonstrated as a useful technique to provide cardiac chamber opacification and to improve left ventricular endocardial border delineation in patients with suboptimal acoustic window, increasing the accuracy and reproducibility of regional and global left ventricular function assessment (Figure 1).5 Clear indications regarding the use of contrast agents for left ventricular opacification are provided by both the American Society of Echocardiography and the European Association of Echocardiography.6, 7 The use of echo contrast agents is recommended in patients having at least two contiguous segments not evaluable on non-contrast images and in patients requiring accurate assessment of left ventricular ejection fraction, regardless of image quality on non-contrast images, in order to increase the accuracy of the assessment of left ventricular volumes and regional and global function. Other indications of contrast echocardiography include confirmation/exclusion of left ventricular structural abnormalities and intracardiac masses, and enhancement of Doppler signals.

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Contrast echocardiography

NUCIFORA

Table I.—Main clinical applications of contrast echocardiography. Left ventricular opacification - Assessment of left ventricular volumes and systolic function - Evaluation of cardiac structures (thrombi and other intracardiac masses) - Evaluation of various cardiomyopathies - Evaluation of mechanical complications of myocardial infarction - Enhancement of Doppler signals - Stress echocardiography


Myocardial contrast echocardiography - Suspected acute myocardial ischemia - After acute myocardial infarction (to predict left ventricular segmental functional recovery, left ventricular remodeling and prognosis) - Chronic ischemic left ventricular dysfunction (to detect myocardial viability) - Stress myocardial contrast echocardiography

volumes is mainly related to the suboptimal recognition of the endocardial border, to the use of off-axis imaging planes and to the foreshortening of the left ventricular apex.17 To date, several studies have shown that contrast echocardiography improves the accuracy of evaluation of left ventricular volumes and left ventricular ejection fraction, comparing favorably with cardiac magnetic resonance.9, 10, 14, 15 Also, left ventricular function and volume assessed by contrast echocardiography demonstrate a lower interobserver variability.15 Regarding the assessment of left ventricular regional wall motion, contrast echocardiography has been show to be the most accurate technique, when compared with cardiac magnetic resonance and cineventriculography.18 The improvement in endocardial border delineation and in the accuracy of estimation of left ventricular volumes and ejection fraction provided by contrast echocardiography has a strong clinical impact in different settings.19, 20 This holds true for patients in whom accurate left ventricular ejection fraction assessment is crucial for decisionmaking and risk stratification (such as patients receiving chemotherapy and patients with recent myocardial infarction, in whom left ventricular ejection fraction is one of the major determinants not only of outcome but also for the implantation of a cardio-

Assessment of left ventricular function

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One of the main advantages of contrast echocardiography is the ability to more accurately quantify left ventricular volumes and global systolic function, as compared to non-enhanced echocardiography.8-14 Indeed, non-enhanced echocardiography, as compared to the accepted gold standard of cardiac magnetic resonance, underestimates left ventricular volumes by 30-40% and left ventricular ejection fraction by 3-6%;9, 11, 15, 16 the underestimation of left ventricular

Figure 1.—A) Non-enhanced echocardiographic study (four-chamber apical view) with poor left ventricular endocardial border definition; B) the use of echo contrast agent provides cardiac chamber opacification and improve left ventricular endocardial border delineation.

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P=0.004

P=0.008

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P=0.004

P=0.009


10 8

P=NS

12 P=NS

Global chi-square

14

6 4

UDV

ESV

CE

UE

Clinical

CE

UE

Clinical

IN C ER O V P A Y R M IG E H DI T C ® A CE

UE

0

Clinical

2

trast echocardiography; in addition, medical therapy was changed in about 11% of the patients, on the basis of the findings of contrast echocardiography. Overall, contrast echocardiography, in this study, had a significant impact on the clinical management on more than one third of the patients. More recently, the use of echo contrast agents has been proposed to improve also the image quality of real-time three-dimensional echocardiography (RT3DE).24 RT3DE has indeed the ability to overcome most of the limitations of two-dimensional echocardiography (including 1) probe positioning error leading to inadequate visualization of true left ventricular apex and foreshortening of images; 2) presence of regional wall motion abnormalities of myocardial regions not displayed in the standard imaging planes and 3) difference between stress imaging planes and corresponding baseline imaging planes, potentially leading to erroneous interpretations).24 However, significant limitations still restrict the widespread use of RT3DE for the assessment of regional and global left ventricular function. Of note, image quality with RT3DE is lower due to suboptimal spatial and temporal resolutions.25, 26 A preliminary study by Collins et al. indeed demonstrated a lower percentage of visualized segments with RT3DE compared to two-dimensional echocardiography (83% vs. 97%, respectively, P20%), being superior to clinical, biochemical, electrocardiographic and angiographic markers and even to low dose dobutamine stress echocardiography.67-71

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cro-vascular flow after reperfusion therapy, while recovery of function is more frequently observed in akinetic segments with normal perfusion.47, 48 Pooled analyses of previously published studies showed high sensitivity (81-82%) but lower specificity (69-74%) of MCE in identifying functional recovery after acute myocardial infarction.47, 48 Several factors could explain the low specificity of MCE: 1) in the first 3-6 hours after reperfusion therapy, reactive hyperemia occurs in areas at last destined to necrosis and produces myocardial opacification during MCE.62 Consequently, MCE performed too early after reperfusion leads to underestimation of the final infarct size and to overestimation of myocardial viability; 2) micro-embolic phenomena to distal vessels can occur during percutaneous coronary intervention, leading to transient and reversible micro-vascular stunning;63 consequently, dynamic changes of MCE perfusion pattern can be observed for up to 48 hours after reperfusion;63 3) acute myocardial infarction involving more than 20% of the subendocardium can hamper functional recovery despite MCE evidence of adequate subepicardial perfusion.2 Performing MCE at least 48 hours after reperfusion, when reactive hyperemia and dynamic changes of micro-vascular perfusion have been subsided, can improve the specificity of the technique.2 Prolonging the assessment of contrast intensity for up to 15 cardiac cycles after micro-bubble destruction can also improve the accuracy of MCE, overcoming the limitation related to the variability of myocardial blood flow in the infarct-related territory.64 Combined assessment of microvascular integrity by MCE and contractile reserve by dobutamine stress echocardiography can further enhance differentiation of stunning and necrosis after AMI, achieving the optimal diagnostic accuracy in case of concordant results.65, 66 Left

ventricular remodeling

Extent and severity of micro-vascular damage after acute myocardial infarc-

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Prognosis

The presence of no-reflow phenomenon, besides correlating to infarct size, can provide prognostic information. Previous studies assessed the prognostic value of myocardial contrast echocardiography after acute myocardial infarction.72-74 Ito et al.16 showed that clinical complications early after anterior acute myocardial infarction, including pericardial effusion and congestive heart failure, are more commonly observed among patients with noreflow after reperfusion, as compared to those with MCE evidence of reflow. More recently, Khumri et al.73 found that patients with first anterior acute myocardial infarction and residual left ventricular dysfunction are at high risk of death during long-term follow-up, in the presence of abnormal perfusion; furthermore, the extent of microvascular damage at MCE was selected as the only predictor of late all-cause mortality, being of incremental value over clinical and angiographic variables. The prognostic value of MCE has been further confirmed by Dwivedi et al.;74 in their study, the extent of perfusion defect during MCE performed early after acute myocardial infarction was an independent predictor of cardiac death and acute myocardial infarction, being of incremental value especially among patients with ejection fraction ≤50%.


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Myocardial contrast echocardiography in chronic ischemic left ventricular dysfunction

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Identification of hibernating myocardium in the setting of chronic ischemic left ventricular dysfunction is extremely important, because restoration of coronary flow leads to left ventricular functional recovery, improves symptoms and reduces the risks of future events.75 Traditionally, contractile response during low-dose dobutamine stress echocardiography has been used to assess myocardial viability. However, this technique has significant limitations: 1) in the presence of severe stenosis, the occurrence of ischemia can precede contractile response; 2) the use of low-dose dobutamine assesses viability of endocardial fibers, potentially ignoring mid- or epicardial viability. Few previous studies analyzed the ability of intracoronary and intravenous MCE to detect hibernating myocardium, using recovery of resting function after myocardial revascularization as end-point.76-79 Both qualitative and quantitative MCE have been shown to have excellent sensitivity (8194%) but lower specificity (49-67%), especially when compared to the occurrence of biphasic response during dobutamine stress echocardiography.76-79 Extensive fibrosis despite relative preservation of capillaries and MCE detection of viability in regions other than endocardium that do not necessarily contribute to resting left ventricular function could explain these findings. Korosoglou et al.2 showed that integration of MCE perfusion data with contractile response during dobutamine stress echocardiography can potentially improve the accuracy of viability assessment, but further studies are needed to confirm this finding.

nary artery disease by detecting abnormal myocardial blood flow reserve.54-56 Taking into account that MCE assesses myocardial perfusion at the capillary level, identification of functionally-relevant coronary artery stenosis with MCE relies on the detection of regional abnormalities of capillary blood volume or myocardial blood velocity during pharmacologic or exercise stress. Historically, diagnosis of significant coronary artery disease with MCE has relied on the subjective evaluation of relative micro-bubbles refilling rates and/or steady-state myocardial contrast intensity during stress as compared to rest condition. This approach has been previously demonstrated to provide equivalent sensitivity and specificity for the diagnosis of coronary artery disease compared to single photon emission computed tomography (SPECT).54 Similarly, quantitative MCE assessment of myocardial blood velocity and myocardial blood flow has been demonstrated to correlate with coronary Doppler flow wire-derived average peak velocity reserve and with quantitative perfusion imaging using positron emission tomography (PET), respectively.80, 81 Overall, pooled analysis of previous studies comparing the accuracy of MCE with that of coronary angiography revealed a mean sensitivity of 82% and specificity of 80% for the diagnosis of flow-limiting coronary artery disease.4 Importantly, MCE has also a prognostic value in stable patients with coronary artery disease; myocardial perfusion assessment indeed provides incremental prognostic information over wall motion analysis, underlining the value of incorporating MCE in stress echocardiography.82

Detection of stable coronary artery disease with stress-rest myocardial contrast echocardiography The use of MCE during vasodilator stress, dobutamine or exercise, allows the identification of stress-induced flow-limiting coronary stenosis in patients with stable coro-

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Myocardial contrast real-time three-dimensional echocardiography While the clinical utility of two-dimensional MCE is well established, the feasibility of 3D assessment of myocardial perfusion is still under investigation (Figure 9).24 RT3DMCE has the potential to overcome many of the limitations of two-dimensional MCE; in particular, it would allow faster image acquisition and off-line assessment of infinite


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Figure 9.—A) RT3D-MCE shows (arrows) an apical perfusion defect; B) an occluded left anterior descending artery with some late filling was subsequently observed at coronary angiography. From Bhan et al.,86 with permission.min cardio 3147.

and RT3D-MCE. Myocardial perfusion could be assessed in 95% of segments during RT3DE vs. 98% of segments during 2DMCE (P=0.006). On the basis of the current knowledge, RT3D-MCE, despite promising, still requires further validation before becoming part of routine clinical practice. In particular, its use for non-invasive evaluation of myocardial perfusion and diagnosis of coronary artery disease needs to be validated against reference techniques (i.e., single-photon emission computed tomography and invasive coronary angiography) in larger studies.24

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planes. 24 However, few studies have provided preliminary data on its application in clinical practice. Toledo et al. tested the applicability of RT3D-MCE in evaluating adenosine-induced changes in myocardial perfusion in eight healthy volunteers and found a twofold increase in the measured perfusion index after adenosine infusion, as expected in physiologic vasodilator response.83 More recently, the feasibility of RT3D-MCE was evaluated in clinical settings.84-86 Iwakura et al. performed 2D and RT3D-MCE after intracoronary injection of microbubbles in 47 patients who underwent primary percutaneous coronary intervention for acute myocardial infarction.84 Myocardial perfusion assessed by RT3D-MCE correlated with infarct size (determined by peak creatine kinase) and predicted regional recovery at follow-up better than 2D-MCE.84 Abdelmoneim and colleagues evaluated the diagnostic accuracy of adenosine 2D and 3D-MCE in a small population (N.=30) of patients with known or suspected coronary artery disease that was referred for single-photon emission computed tomography.85 When comparing MCE with singlephoton emission computed tomography, sensitivity and specificity were comparable for both 2D and 3D-MCE (~90% and 75%, respectively).85 However, as shown by Bhan et al., the feasibility of RT3D-MCE is still lower than that of 2D-MCE.86 In that study, 46 patients referred for dobutamine stress echocardiography underwent 2D

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Conclusions

The use of echo contrast agents significantly improves imaging in routine echocardiography and stress echocardiography, enhancing the diagnostic accuracy. Contrast echocardiography is also cost effective, reducing the need of further diagnostic tests and sparing the patient further invasive and potentially harmful investigations. The benefits of the use of echo contrast agents include also the possibility to measure myocardial perfusion in different clinical settings. Riassunto

Applicazioni correnti dell’ecocardiografia transtoracica L’ecocardiografia transtoracica è una tecnica d’immagine non-invasiva largamente diffusa, in grado di fornire informazioni concernenti la struttura e alla funzione cardiaca in condizioni di riposo e sotto stress. Tuttavia, in una percentuale non trascurabile di pazienti non sono ottenibili immagini utili dal punto di vista diagnostico, soprattutto a causa dell’obesità e di malattie polmonari. L’utilizzo di mezzi di contrasto ecografici (costituiti da microbolle composte di gas ad alto peso molecolare incapsulato in un involucro esterno e dotate di caratteristiche ultrasonografiche nettamente distinte da quelle delle cellule del sangue e dei tessuti circostanti) risolve questi problemi, determinando l’opacizzazione della camera cardiaca e migliorando la definizione del bordo endocardico, e conseguentemente permettendo una quantificazione più


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spective, randomly assigned, blinded study. J Am Coll Cardiol 2001;38:867-75. 12. Nahar T, Croft L, Shapiro R, Fruchtman S, Diamond J, Henzlova M et al. Comparison of four echocardiographic techniques for measuring left ventricular ejection fraction. Am J Cardiol 2000;86:1358-62. 13. Yu EH, Sloggett CE, Iwanochko RM, Rakowski H, Siu SC. Feasibility and accuracy of left ventricular volumes and ejection fraction determination by fundamental, tissue harmonic, and intravenous contrast imaging in difficult-to-image patients. J Am Soc Echocardiogr 2000;13:216-24. 14. Lim TK, Burden L, Janardhanan R, Ping C, Moon J, Pennell D et al. Improved accuracy of low-power contrast echocardiography for the assessment of left ventricular remodeling compared with unenhanced harmonic echocardiography after acute myocardial infarction: comparison with cardiovascular magnetic resonance imaging. J Am Soc Echocardiogr 2005;18:1203-7. 15. Hoffmann R, von Bardeleben S, ten Cate F, Borges AC, Kasprzak J, Firschke C et al. Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography. Eur Heart J 2005;26:607-16. 16. Jenkins C, Moir S, Chan J, Rakhit D, Haluska B, Marwick TH. Left ventricular volume measurement with echocardiography: a comparison of left ventricular opacification, three-dimensional echocardiography, or both with magnetic resonance imaging. Eur Heart J 2009;30:98-106. 17. Chahal NS, Senior R. Clinical applications of left ventricular opacification. JACC Cardiovasc Imaging 2010;3:188-96. 18. Hoffmann R, von Bardeleben S, Kasprzak JD, Borges AC, ten Cate F, Firschke C et al. Analysis of regional left ventricular function by cineventriculography, cardiac magnetic resonance imaging, and unenhanced and contrast-enhanced echocardiography: a multicenter comparison of methods. J Am Coll Cardiol 2006;47:121-8. 19. Kurt M, Shaikh KA, Peterson L, Kurrelmeyer KM, Shah G, Nagueh SF et al. Impact of contrast echocardiography on evaluation of ventricular function and clinical management in a large prospective cohort. J Am Coll Cardiol 2009;53:802-10. 20. Dwivedi G, Janardhanan R, Hayat SA, Lim TK, Senior R. Improved prediction of outcome by contrast echocardiography determined left ventricular remodelling parameters compared to unenhanced echocardiography in patients following acute myocardial infarction. Eur J Echocardiogr 2009;10:933-40. 21. Galema TW, Geleijnse ML, Yap SC, van Domburg RT, Biagini E, Vletter WB et al. Assessment of left ventricular ejection fraction after myocardial infarction using contrast echocardiography. Eur J Echocardiogr 2008;9:250-4. 22. Nucifora G, Marsan NA, Siebelink HM, van Werkhoven JM, Schuijf JD, Schalij MJ et al. Safety of contrastenhanced echocardiography within 24 h after acute myocardial infarction. Eur J Echocardiogr 2008;9:8168. 23. Reilly JP, Tunick PA, Timmermans RJ, Stein B, Rosenzweig BP, Kronzon I. Contrast echocardiography clarifies uninterpretable wall motion in intensive care unit patients. J Am Coll Cardiol 2000;35:485-90. 24. Ng AC, Delgado V, Bertini M, Nucifora G, Shanks M, Ajmone Marsan N et al. Advanced applications of 3-dimensional echocardiography. Minerva Cardioangiol 2009;57:415-41.


precisa della funzione ventricolare sinistra. Oltre a migliorare la valutazione della funzione ventricolare sinistra, i mezzi di contrasto ecografici possono essere usati anche per valutare la perfusione miocardica a livello capillare, fornendo informazioni utili sul flusso ematico miocardico. Scopo del presente lavoro è di fornire una panoramica delle principali applicazioni cliniche dell’ecocardiografia con contrasto, cioè l’opacizzazione del ventricolo sinistro e la valutazione della perfusione miocardica. Parole chiave: Ecocardiografia - Cuore, ventricoli Miocardio, perfusione, imaging.

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