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Use of transesophageal contrast echocardiography for excluding left atrial appendage thrombi in patients with atrial fibrillation before cardioversion
Use of Transesophageal Contrast Echocardiography for Excluding Left Atrial Appendage Thrombi in Patients with Atrial Fibrillation Before Cardioversion Giso von der Recke, Harald Schmidt, MD, Stefan Illien, MD, Berndt Lu¨deritz, MD, FACC, and Heyder Omran, MD, Bonn, Germany
Transesophageal echocardiographic (TEE) guidance of cardioversion in patients with atrial fibrillation is an alternative method to conventional anticoagulation. Although TEE is considered the gold standard for excluding left atrial (LA) thrombi, in some patients dense spontaneous echo contrast (SEC) and artifacts may hamper the identification or exclusion of LA thrombi. Often those patients are refused cardioversion. The purpose of this study was to determine whether the application of echo contrast (Optison, Mallinckrodt, San Diego, Calif) facilitates the exclusion of LA appendage thrombi in this patient group and allows for safer cardioversion. Forty-one patients with atrial fibrillation and dense SEC or inconclusive TEE findings were given echo contrast. Fourteen patients with sinus rhythm served as control participants. Echo contrast com-
A transesophageal echocardiographic (TEE)-guid-
ed approach to cardioversion of atrial fibrillation (AF) is considered to have a similar safety profile as that of conventional anticoagulation therapy.1 However, definitive exclusion of left atrial (LA) thrombi by TEE is not feasible in all patients. Especially in patients with dense spontaneous echo contrast (SEC), the cavity of LA appendage may not be adequately visualized. In addition, artifacts in LA appendage caused by reveberations of the limbus of the left pulmonary vein may hamper the exclusion of LA thrombi. As a consequence, patients with dense SEC or inconclusive TEE findings are often excluded from cardioversion. Second-generation ultrasound contrast agents, capable of passing through the pulmonary capillaries, have been shown to improve delineation of the left endocardial contour and reduce artifacts in the left From the Department of Medicine-Cardiology, University of Bonn. Reprint requests: Heyder Omran, MD, Department of Medicine Cardiology, University of Bonn, Sigmund-Freud-Str. 25, D 53105 Bonn, Germany (E-mail: [email protected]). Copyright 2002 by the American Society of Echocardiography. 0894-7317/2002/$35.00 ⫹ 0 27/1/123961 doi:10.1067/mje.2002.123961
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pletely reduced artifacts in 13 of 22 patients. In 12 of 19 patients with SEC, the LA appendage was completely filled after the application of echo contrast and, thus, SEC was completely suppressed. In 13 of 41 patients, it was filled incompletely and in 9 of 41 patients, a new mass resembling a thrombus was detected. In total, of 25 of 41 patients with inconclusive TEE findings an atrial thrombus was definitively excluded. Those patients underwent cardioversion. None of those patients had a cerebral embolic complication as assessed by cranial magnetic resonance imaging. Thus, the application of echo contrast may facilitate the TEE exclusion of LA appendage thrombi and, hence, improve the safety of TEEguided cardioversion. (J Am Soc Echocardiogr 2002; 15:1256-61.)
ventricle.2 In addition, a case report has been published recently that presents patients in whom echo contrast yielded the identification of left-sided thrombi.3 The purpose of this study was to evaluate whether contrast TEE improves the identification, exclusion, or both of LA appendage thrombi in patients with AF before cardioversion.
METHODS Study Patients The study was conducted as a prospective study at a tertiary cardiac referral center. Between January 1999 and September 2000, 121 patients underwent TEE for the exclusion of LA thrombi before cardioversion. In 41 of 121 patients exclusion of LA appendage thrombi was difficult because of either dense SEC (n ⫽ 19) or artifacts in the LA appendage (n ⫽ 22). Those patients formed the study group and were investigated by contrast TEE to evaluate the use of echo contrast on excluding LA appendage thrombi. Those patients with definitive exclusion of LA appendage thrombi by the use of contrast echocardiography underwent cardioversion. The incidence of cerebral embolism was assessed by cranial magnetic resonance
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imaging. Patients with definitive identification of a LA appendage thrombus and or contraindications to a TEE study were excluded from the study. Fourteen patients in sinus rhythm served as control participants. The study was approved by the institutional review board of the University of Bonn. Echocardiographic Studies All studies were conducted with commercially available equipment (System V, General Electric, Horton, Norway), as previously described.4 Transthoracic echocardiographic (TTE) studies were performed with an 1.7- to 3.4-MHz harmonic transducer and a 6.7-MHz multiplane probe was used for the TEE studies. Echocardiographic evaluations were performed by an investigator who was blinded to the clinical data. For offline quantitative assessment of the echocardiographic data, examinations were digitized and transferred to a computer for subsequent analysis by means of the evaluation software provided by the manufacturer (Echopac, GE, USA). Ultrasound Contrast Agent Optison (Mallinckrodt, San Diego, Calif) is a commercially available second-generation contrast agent containing octafluorpropane-filled microspheres. Each milliliter of Optison (Mallinckrodt) contains 5.0 to 8.0 ⫻ 108 microspheres with a mean range of 2.0 to 4.5 m. This size allows the microspheres to pass unimpeded through the pulmonary capillaries and to reach the LA for sufficient contrast during ultrasound exposure. Optison (Mallinckrodt) is fully manufactured before being filled into 3 mL single-use vials.5 Before injection, Optison (Mallinckrodt) was resuspended as determined by rolling the vial horizontally between the palms. A total of 1 mL Optison (Mallinckrodt) was filled into a 1-mL syringe without further dilution. TTE and TEE Studies and Measurements M-mode TTE was used to measure the LA dimension in the parasternal long-axis view according to the recommendations of the North American Society of Echocardiography.6 The left ventricular ejection fraction was determined by Simpson’s rule.7 Multiplane TEE was performed to visualize the LA chamber and appendage, and parameters were measured as previously described.4 In short, the maximal and minimal LA appendage area were measured and LA appendage ejection fraction was calculated. Peak emptying velocities were measured by placing the sample volume of the pulse waved Doppler approximately 1 cm into the orifice; peak emptying wavelets were measured in 5 consecutive cycles, and maximal velocities then averaged. We searched thoroughly for thrombi and SEC. The presence of SEC was graded from 0 to 4⫹.8 In the case of thrombi, the maximal length and width, the mobility, and its echodensity were recorded. After completion of the conventional TEE study, a study with echo contrast was performed. The mechanic index was set to 0.4.9 Therefore, a syringe was placed into the
von der Recke et al 1257
right or left cubital vein. Optison (Mallinckrodt) was flushed as a 0.5-mL bolus injection, followed by an injection of 2 mL saline solution. The filling of the LA chamber and appendage was observed and classified as rapid and complete filling of the LA appendage, delayed and incomplete filling, or no filling of the LA appendage. In addition, peak emptying velocities of the LA appendage were measured after Optison (Mallinckrodt) application. The quality of the signal was compared with the recording without echo contrast. Improvement of the Doppler signal was defined as “present” or “absent.” Furthermore, the effect of echo contrast on the reduction of artifacts in the LA appendage was determined and graded from 0 (no reduction) to 2 (complete suppression) of the artifact. In patients with dense SEC, the LA appendage was carefully searched for thrombi after the application of echo contrast. Statistical Analysis Data are reported as the mean ⫾ SD. Continuous variables between groups were compared by the Student t test for unpaired observations. Nominal data were compared by the Fisher exact test. A P value ⱕ .05 was considered statistically significant. Software used was StatView 5.0 (Abacus Inc, Berkeley, Calif).
RESULTS Patients During the study period, 121 patients underwent TEE for the exclusion of LA appendage thrombi before cardioversion. Sixty-six patients (55%) had previous cardioversion attempts, 75 patients (61%) had a duration of AF more than 3 months. In 13 of the 121 patients (11%), a LA appendage thrombus was identified. In 41 patients (34%; 33 men, age: 66.2 ⫾ 9.5 years old), ambiguous findings lead to inclusion in the study group. Of those, 23 patients had coronary artery disease, 7 patients had a cardiomyopathy, and 5 patients had valvular disease. Fourteen patients with in sinus rhythm served as control participants. Twenty-two patients received phenprocoumon, and 9 patients were treated with intravenous heparin. Twelve patients had an INR greater than 2, and 9 patients a partial thromboplastin time greater than 1.5 of the control value. Five patients had a history of cerebral embolism. TTE Parameters The mean LA diameter was 5.05 ⫾ 0.75 cm in patients with AF compared with 3.88 ⫾ 1.14 cm in patients with in sinus rhythm (P ⫽ .0002). The respective values for left ventricular ejection fraction were 52.2% ⫾ 18.7% in the AF group and 68.4% ⫾ 9.7% in the patients with in sinus rhythm (P ⫽ .0047).
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Figure 1 A, Dense spontaneous echo contrast restricts full view into LA appendage. B, Tip of left atrial appendage is inconclusive. Is this artifact (arrow)?
TEE Without Echo Contrast Patients with AF had larger maximal LA appendage areas than patients with in sinus rhythm (5.22 ⫾ 2.7 cm2 vs 3.78 ⫾ 1.1 cm2; P ⫽ .065). Furthermore, they had lower LA appendage ejection fractions (18% ⫾ 12% vs 39% ⫾ 14%; P ⬍ .0001) and lower peak emptying velocities of the LA appendage (0.29 ⫾ 0.17 m/s vs 0.69 ⫾ 0.15 m/s; P ⬍ .0001) than patients with in sinus rhythm. The incidence of SEC was significantly lower in patients with in sinus rhythm than in patients with AF (P ⫽ .0082). The grade of SEC was distributed in the study group as follows: grade 0 ⫽ 13 patients (29%); grade 1⫹ ⫽ 7 (17%); grade 2⫹ ⫽ 6 (15%); grade 3⫹ ⫽ 7 (17%); grade 4⫹ ⫽ 9 (22%). SEC was not present in 13 of 14 patients with in sinus rhythm. Only 1 patient with in sinus rhythm had grade 2⫹ SEC. In 19 (46%) patients with AF, dense SEC partially blurred the vision of the LA appendage (Figure 1, A). In the other 22 (54%) patients of the study group, artifacts from the limbus of the left upper pulmonary vein restricted complete visualization of the LA appendage (Figure 1, B). TEE with Echo Contrast After the application of echo contrast, none of the patients experienced any side effects. A gradual filling of the LA chamber and a consecutive filling of the LA appendage was observed in all patients. From the beginning of the appearance of echo contrast until maximal filling of the LA appendage, less than 20 heart cycles were required in all patients. However, echo contrast did not fill the LA appendage in all patients. A complete filling of the LA appendage was observed in 27 (66%) patients of the study group, 13 (32%) patients showed only a partial filling, and 1 (2%) none at all, whereas echo contrast filled the LA appendage in all patients with in sinus rhythm. The filling of the LA appendage with echo
contrast took longer in patients with AF than in those with in sinus rhythm (13 ⫾ 7 vs 9 ⫾ 5 heart cycles; P ⬍ .001). In the 19 patients with dense SEC, the use of echo contrast initially enhanced the curling blood flow pattern. Then, after maximal flooding of the LA cavity, the curling pattern was suppressed and replaced by a homogenous appearance of the echo contrast. Dense SEC in the LA appendage was completely suppressed in 12 (63%) of the 19 patients, partially suppressed in 3 (16%) patients, and in the remaining 4 (21%) patients not all (Figure 2, A). Thus, the exclusion of a LA appendage thrombus could be confirmed in 12 of the 19 patients with dense SEC by means of echo contrast application. In the 22 patients with artifacts from the limbus of the upper left pulmonary vein, complete suppression of the artifacts by the microbubbles was yielded in 13 (59%) patients and partial suppression in 3 (14%) patients. Six (27%) patients did not show any suppression at all (Figure 2, B). Consequently, LA appendage thrombi could be excluded in 13 patients by the use of echo contrast. In total, the use of echo contrast resulted in the definitive exclusion of LA thrombi in 25 of 41 patients (61%). Furthermore, in 9 of the 41 patients, the application of echo contrast resulted in the appearance of a new mass in the tip of the LA appendage that was not visualized by TEE without echo contrast. In those cases the mass was clearly delineated as a recess by the echo contrast. The masses were all mobile, distinct from the curling pattern of SEC, and distinct from the reverberations of the limbus of the pulmonary vein (Figure 3, A and B). The mean diameter and length was 1.2 cm and 0.8 cm, respectively. The patients with thrombi underwent follow up TEE after 4 weeks under continued anticoagulation therapy. In 4 patients, the repeated echo contrast study showed disappearance of the previous mass. In 2 patients without adequate anticoagulation
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Figure 2 A, Echo contrast suppressed spontaneous echo contrast (same patient as in Figure 1, A) and completely opacified left atrial appendage. B, Previous artifacts (same patient as in Figure 1, B) have been suppressed by echo contrast.
therapy, TEE without echo contrast already revealed a thrombus, located in the same position as the previously described mass. The use of echo contrast did improve the quality of the Doppler signal over the LA appendage in 19 of 41 patients (46%) and in 6 of 14 control participants (46%). However, measurement of peak emptying velocities of the LA appendage with and without echo contrast did not differ significantly (0.30 ⫾ 0.17 m/s vs 0.29 ⫾ 0.17 m/s; P ⫽ .42) in the study group. For patients with sinus rhythm, they were recorded as 0.73 ⫾ 0.15 m/s with echo contrast as 0.70 ⫾ 0.16 m/s without echo contrast (P ⫽ .13). Thromboembolic Complications after Cardioversion After exclusion of LA appendage thrombi 25 patients with AF underwent electrical cardioversion. None of them had clinical manifestations of cerebral embolism or cerebral embolism as assessed by cranial magnetic resonance imaging during a follow-up of 7 days after cardioversion.
DISCUSSION TEE-guided cardioversion of AF is an alternative approach to conventional anticoagulation. However, a potential clinical problem is the definitive exclusion of LA thrombi in patients with dense SEC or in patients with artifacts in the LA appendage. This is the first study to investigate the use of echo contrast for excluding LA appendage thrombi in patients with AF scheduled for cardioversion. The results of our study show that the application of intravenous echo contrast during the TEE study improves the capability of excluding LA thrombi in those patients. Echo Contrast for Assessing LA Appendage Morphology and Function Second-generation echo contrast agents with the ability of passing the pulmonary capillaries have been shown to improve the delineation of the left ventricular endocardial border.5 Furthermore, echo
Figure 3 A, Arrows indicate delineation of thrombus by echo contrast. B, Thrombus (arrows) is surrounded by echo contrast and is clearly delineated.
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contrast may be used to facilitate the diagnosis of left ventricular thrombi.10 Two previous studies using Albunex as a contrast agent during a TEE study demonstrated that echo contrast improves the assessment of LA appendage morphology and function.11,12 Kato et al11 reported that the application of echo contrast in patients with AF and a history of cerebral embolism may be associated with incomplete opacification of the LA appendage. Those patients with dense SEC more often had incomplete opacification of the LA appendage than those patients without SEC. Our finding of incomplete filling of the LA appendage by Optison (Mallinckrodt) in selected patients with dense SEC support the findings of Kato et al.11 In this respect our results confirm the conclusion of Kato et al11 that incomplete opacification of the LA appendage indicates a hemodynamic stasis in the LA appendage. Nevertheless, in our study 63% of patients with dense SEC showed complete opacification of the LA appendage by the use of Optison (Mallinckrodt). A potential explanation for this difference in findings is that Optison (Mallinckrodt) is a more advanced echo contrast agent with a better contrast effect and higher stability.2,13 Furthermore, we used a low mechanic index resulting in lesser destruction of the contrast agent.9 Those factors may have contributed to a better contrast effect of the used contrast agent in the LA appendage. Often the exclusion of LA appendage thrombi is difficult in patients with SEC. Our finding that a modern contrast agent may allow complete opacification of the LA appendage even in the presence of SEC is therefore of clinical importance. Complete echo contrast opacification of the LA appendage may allow excluding LA appendage thrombi with a high degree of confidence. A similar problem of reliable exclusion of LA appendage thrombi is present when artifacts occur in the cavity of the LA appendage. Those artifacts are often caused by reverberations of the limbus of the left pulmonary vein. We observed the presence of artifacts in 51% of patients in our study cohort. Interestingly, the application of echo contrast diminished these artifacts in the majority of patients. Thus, echo contrast may also be useful for excluding LA appendage thrombi when artifacts are present. Another finding of our study is that the use of echo contrast resulted in the improvement of the quality of the Doppler signal over the LA appendage in 46% of patients. This finding is in congruence with the results of Yao et al12 who showed an improvement of the Doppler signal in 63% of cases. In concordance with that study, we did not find a significant difference in peak emptying velocities of LA appendage as measured with and without echo contrast.
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Echo Contrast for Delineating LA Thrombi Diagnosing LA appendage thrombi in the presence of SEC may be difficult. Furthermore, LA appendage thrombi with low echodensity may be missed by conventional echocardiography. A recent case report applying harmonic power Doppler contrast echocardiography demonstrated the depiction of an atrial thrombus that was missed by conventional TEE imaging.3 The results of our study show that the use of echo contrast in patients with dense SEC may result in the delineation of masses resembling thrombi. There are several arguments that those masses actually represent thrombi. First, the structures were mobile and had a silhouette resembling a thrombus in size and shape. Second, we observed the disappearance of those masses under continued effective anticoagulation therapy after a 4-week follow-up. On the other hand, in 2 patients with ineffective anticoagulation we observed the development of thrombi with increased echogenicity already visible with conventional TEE. Those thrombi had the same appearance as the previously diagnosed masses by contrast echocardiography. A third argument supporting the hypothesis that those phenomena are a result of thrombi and not a result of stasis is that the echo contrast agent fills around those structures (Figure 3, B). Whereas in patients with incomplete filling of the LA appendage because of decreased blood flow velocities, the pattern of the echo contrast enhancement differed. In those cases the echo contrast filled only the body of the LA appendage in a curtain like manner. Thanigaraj et al10 reported similar findings with respect to left ventricular thrombi. In their study, echo contrast smoothly delineated the left ventricular endocardium in the absence of thrombi. In the presence of thrombi this delineation became irregular. Furthermore, they found no case where contrast enhancement mimicked or masqueraded a left ventricular thrombus.10 Echo Contrast for the Exclusion of LA Thrombi by TEE Before Cardioversion This is the first study to evaluate the use of echo contrast for excluding LA thrombi in patients scheduled for cardioversion. The results of our study show that the application of echo contrast facilitates the exclusion of LA thrombi in patients with dense SEC or in patients with artifacts in the LA appendage. Artifacts in the LA appendage as produced by reverberations of the limbus of the left pulmonary vein are a potential clinical problem and may mimic LA appendage thrombi, resulting in the false positive diagnosis of an atrial thrombus. As a consequence those patients may be excluded from cardioversion. Our results show that the application of echo contrast reduces artifacts because of reverberations in
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the majority of patients. Thus, a reliable exclusion of LA appendage thrombi is ensured in those cases. SEC represents a low-flow phenomenon in the LA appendage.14 In patients with dense SEC the tip of the LA appendage often can not be completely visualized and an exclusion of a thrombus is difficult. Our findings show that a stable contrast agent may allow for delayed, but complete opacification of the LA appendage. Thus, the exclusion of a thrombus may be confirmed. In this respect it is interesting that none of our patients with exclusion of LA appendage thrombi by means of echo contrast had thromboembolic complications after cardioversion of AF.
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3.
4.
5. 6.
Clinical Implications The finding of our study that a second-generation echo contrast agent may enhance the exclusion or identification of LA appendage thrombi by means of TEE in patients with suboptimal conventional TEE examinations provides a valuable contribution to more comprehensive treatment decision in those patients. This fact is underlined by our finding that none of the patients who underwent cardioversion of AF had thromboembolic complications afterward.
7. 8.
9.
Limitations 10.
A potential limitation of our study is that we could not use anatomical validation for excluding or identifying LA appendage thrombi. Furthermore, contrast echocardiography does not allow for the differentiation of small thrombi from trabeculation. Thus, definitive proof of the presence of thrombi as diagnosed by echo contrast TEE is not possible. However, we did not observe thromboembolic complications after echo contrast TEE-guided exclusion of LA thrombi. REFERENCES 1. Klein AL, Grimm RA, Black IW, Leung DY, Chung MK, Vaughn SE, et al. Cardioversion guided by transesophageal echocardiography, the ACUTE Pilot Study; a randomized, controlled trial: assessment of cardioversion using transesophageal echocardiography. Ann Intern Med 1997;126:200-9. 2. Cohen JL, Cheirif J, Segar DS, Gillam LD, Gottdiener JS,
11.
12.
13.
14.
Hausnerova E, et al. Improved left ventricular endocardial border delineation and opacification with Optison(FS069), a new echocardiographic contrast agent: results of a phase III multicenter trial. J Am Coll Cardiol 1998;32:746-52. Bednarz JE, Spencer KT, Weinert L, Sugeng L, Mor-Avi V, Lang RM. Identification of cardiac masses and abnormal blood flow patterns with harmonic power Doppler contrast echocardiography. J Am Soc Echocardiogr 1999;12:871-5. Omran H, Jung W, Rabahieh R, Wirtz P, Becher H, Illien S, et al. Imaging of thrombi and assessment of left atrial appendage function: a prospective study comparing transthoracic and transoesophageal echocardiography. Heart 1999;81:192-8. Clark LN, Dittrich HC. Cardiac imaging using Optison. Am J Cardiol 2000;86:14-8G. Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp RL, et al. Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Twodimensional Echocardiography. Circulation 1980;62:212-5 Weyman AE. Principles and practice of echocardiography. 2nd ed. Philadelphia: Lea & Febiger; 1994. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961-9. Wible JH Jr, Wojdyla JK, Hughes MS, Brandenburger GH. Effects of transducer frequency and output power on the ultrasonographic contrast produced by Optison using fundamental and harmonic imaging techniques. J Ultrasound Med 1999;18:753-62. Thanigaraj S, Schechtman KB, Perez JE. Improved echocardiographic delineation of left ventricular thrombus with the use of intravenous second-generation contrast image enhancement. J Am Soc Echocardiogr 1999;12:1022-6. Kato H, Nakanishi M, Maekawa N, Ohnishi T, Yamamoto M. Evaluation of left atrial appendage stasis in patients with atrial fibrillation using transesophageal echocardiography with an intravenous albumin-contrast agent. Am J Cardiol 1996;78: 365-9. Yao SS, Ilercil A, Meisner JS, Strom JA, Shirani J. Improved Doppler echocardiographic assessment of the left atrial appendage by peripheral vein injection of sonicated albumin microbubbles. Am Heart J 1997;133:400-5. Skyba DM, Camarano G, Goodman NC, Price RJ, Skalak TC, Kaul S. Hemodynamic characteristics, myocardial kinetics and microvascular rheology of FS-069, a second-generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection. J Am Coll Cardiol 1996;28:1292-300. Black IW. Spontaneous echo contrast: where there’s smoke there’s fire. Echocardiography 2000;17:373-82.
Transesophageal echocardiographic (TEE) guidance of cardioversion in patients with atrial fibrillation is an alternative method to conventional anticoagulation. Although TEE is considered the gold standard for excluding left atrial (LA) thrombi, in some patients dense spontaneous echo contrast (SEC) and artifacts may hamper the identification or exclusion of LA thrombi. Often those patients are refused cardioversion. The purpose of this study was to determine whether the application of echo contrast (Optison, Mallinckrodt, San Diego, Calif) facilitates the exclusion of LA appendage thrombi in this patient group and allows for safer cardioversion. Forty-one patients with atrial fibrillation and dense SEC or inconclusive TEE findings were given echo contrast. Fourteen patients with sinus rhythm served as control participants. Echo contrast com-
A transesophageal echocardiographic (TEE)-guid-
ed approach to cardioversion of atrial fibrillation (AF) is considered to have a similar safety profile as that of conventional anticoagulation therapy.1 However, definitive exclusion of left atrial (LA) thrombi by TEE is not feasible in all patients. Especially in patients with dense spontaneous echo contrast (SEC), the cavity of LA appendage may not be adequately visualized. In addition, artifacts in LA appendage caused by reveberations of the limbus of the left pulmonary vein may hamper the exclusion of LA thrombi. As a consequence, patients with dense SEC or inconclusive TEE findings are often excluded from cardioversion. Second-generation ultrasound contrast agents, capable of passing through the pulmonary capillaries, have been shown to improve delineation of the left endocardial contour and reduce artifacts in the left From the Department of Medicine-Cardiology, University of Bonn. Reprint requests: Heyder Omran, MD, Department of Medicine Cardiology, University of Bonn, Sigmund-Freud-Str. 25, D 53105 Bonn, Germany (E-mail: [email protected]). Copyright 2002 by the American Society of Echocardiography. 0894-7317/2002/$35.00 ⫹ 0 27/1/123961 doi:10.1067/mje.2002.123961
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pletely reduced artifacts in 13 of 22 patients. In 12 of 19 patients with SEC, the LA appendage was completely filled after the application of echo contrast and, thus, SEC was completely suppressed. In 13 of 41 patients, it was filled incompletely and in 9 of 41 patients, a new mass resembling a thrombus was detected. In total, of 25 of 41 patients with inconclusive TEE findings an atrial thrombus was definitively excluded. Those patients underwent cardioversion. None of those patients had a cerebral embolic complication as assessed by cranial magnetic resonance imaging. Thus, the application of echo contrast may facilitate the TEE exclusion of LA appendage thrombi and, hence, improve the safety of TEEguided cardioversion. (J Am Soc Echocardiogr 2002; 15:1256-61.)
ventricle.2 In addition, a case report has been published recently that presents patients in whom echo contrast yielded the identification of left-sided thrombi.3 The purpose of this study was to evaluate whether contrast TEE improves the identification, exclusion, or both of LA appendage thrombi in patients with AF before cardioversion.
METHODS Study Patients The study was conducted as a prospective study at a tertiary cardiac referral center. Between January 1999 and September 2000, 121 patients underwent TEE for the exclusion of LA thrombi before cardioversion. In 41 of 121 patients exclusion of LA appendage thrombi was difficult because of either dense SEC (n ⫽ 19) or artifacts in the LA appendage (n ⫽ 22). Those patients formed the study group and were investigated by contrast TEE to evaluate the use of echo contrast on excluding LA appendage thrombi. Those patients with definitive exclusion of LA appendage thrombi by the use of contrast echocardiography underwent cardioversion. The incidence of cerebral embolism was assessed by cranial magnetic resonance
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imaging. Patients with definitive identification of a LA appendage thrombus and or contraindications to a TEE study were excluded from the study. Fourteen patients in sinus rhythm served as control participants. The study was approved by the institutional review board of the University of Bonn. Echocardiographic Studies All studies were conducted with commercially available equipment (System V, General Electric, Horton, Norway), as previously described.4 Transthoracic echocardiographic (TTE) studies were performed with an 1.7- to 3.4-MHz harmonic transducer and a 6.7-MHz multiplane probe was used for the TEE studies. Echocardiographic evaluations were performed by an investigator who was blinded to the clinical data. For offline quantitative assessment of the echocardiographic data, examinations were digitized and transferred to a computer for subsequent analysis by means of the evaluation software provided by the manufacturer (Echopac, GE, USA). Ultrasound Contrast Agent Optison (Mallinckrodt, San Diego, Calif) is a commercially available second-generation contrast agent containing octafluorpropane-filled microspheres. Each milliliter of Optison (Mallinckrodt) contains 5.0 to 8.0 ⫻ 108 microspheres with a mean range of 2.0 to 4.5 m. This size allows the microspheres to pass unimpeded through the pulmonary capillaries and to reach the LA for sufficient contrast during ultrasound exposure. Optison (Mallinckrodt) is fully manufactured before being filled into 3 mL single-use vials.5 Before injection, Optison (Mallinckrodt) was resuspended as determined by rolling the vial horizontally between the palms. A total of 1 mL Optison (Mallinckrodt) was filled into a 1-mL syringe without further dilution. TTE and TEE Studies and Measurements M-mode TTE was used to measure the LA dimension in the parasternal long-axis view according to the recommendations of the North American Society of Echocardiography.6 The left ventricular ejection fraction was determined by Simpson’s rule.7 Multiplane TEE was performed to visualize the LA chamber and appendage, and parameters were measured as previously described.4 In short, the maximal and minimal LA appendage area were measured and LA appendage ejection fraction was calculated. Peak emptying velocities were measured by placing the sample volume of the pulse waved Doppler approximately 1 cm into the orifice; peak emptying wavelets were measured in 5 consecutive cycles, and maximal velocities then averaged. We searched thoroughly for thrombi and SEC. The presence of SEC was graded from 0 to 4⫹.8 In the case of thrombi, the maximal length and width, the mobility, and its echodensity were recorded. After completion of the conventional TEE study, a study with echo contrast was performed. The mechanic index was set to 0.4.9 Therefore, a syringe was placed into the
von der Recke et al 1257
right or left cubital vein. Optison (Mallinckrodt) was flushed as a 0.5-mL bolus injection, followed by an injection of 2 mL saline solution. The filling of the LA chamber and appendage was observed and classified as rapid and complete filling of the LA appendage, delayed and incomplete filling, or no filling of the LA appendage. In addition, peak emptying velocities of the LA appendage were measured after Optison (Mallinckrodt) application. The quality of the signal was compared with the recording without echo contrast. Improvement of the Doppler signal was defined as “present” or “absent.” Furthermore, the effect of echo contrast on the reduction of artifacts in the LA appendage was determined and graded from 0 (no reduction) to 2 (complete suppression) of the artifact. In patients with dense SEC, the LA appendage was carefully searched for thrombi after the application of echo contrast. Statistical Analysis Data are reported as the mean ⫾ SD. Continuous variables between groups were compared by the Student t test for unpaired observations. Nominal data were compared by the Fisher exact test. A P value ⱕ .05 was considered statistically significant. Software used was StatView 5.0 (Abacus Inc, Berkeley, Calif).
RESULTS Patients During the study period, 121 patients underwent TEE for the exclusion of LA appendage thrombi before cardioversion. Sixty-six patients (55%) had previous cardioversion attempts, 75 patients (61%) had a duration of AF more than 3 months. In 13 of the 121 patients (11%), a LA appendage thrombus was identified. In 41 patients (34%; 33 men, age: 66.2 ⫾ 9.5 years old), ambiguous findings lead to inclusion in the study group. Of those, 23 patients had coronary artery disease, 7 patients had a cardiomyopathy, and 5 patients had valvular disease. Fourteen patients with in sinus rhythm served as control participants. Twenty-two patients received phenprocoumon, and 9 patients were treated with intravenous heparin. Twelve patients had an INR greater than 2, and 9 patients a partial thromboplastin time greater than 1.5 of the control value. Five patients had a history of cerebral embolism. TTE Parameters The mean LA diameter was 5.05 ⫾ 0.75 cm in patients with AF compared with 3.88 ⫾ 1.14 cm in patients with in sinus rhythm (P ⫽ .0002). The respective values for left ventricular ejection fraction were 52.2% ⫾ 18.7% in the AF group and 68.4% ⫾ 9.7% in the patients with in sinus rhythm (P ⫽ .0047).
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Figure 1 A, Dense spontaneous echo contrast restricts full view into LA appendage. B, Tip of left atrial appendage is inconclusive. Is this artifact (arrow)?
TEE Without Echo Contrast Patients with AF had larger maximal LA appendage areas than patients with in sinus rhythm (5.22 ⫾ 2.7 cm2 vs 3.78 ⫾ 1.1 cm2; P ⫽ .065). Furthermore, they had lower LA appendage ejection fractions (18% ⫾ 12% vs 39% ⫾ 14%; P ⬍ .0001) and lower peak emptying velocities of the LA appendage (0.29 ⫾ 0.17 m/s vs 0.69 ⫾ 0.15 m/s; P ⬍ .0001) than patients with in sinus rhythm. The incidence of SEC was significantly lower in patients with in sinus rhythm than in patients with AF (P ⫽ .0082). The grade of SEC was distributed in the study group as follows: grade 0 ⫽ 13 patients (29%); grade 1⫹ ⫽ 7 (17%); grade 2⫹ ⫽ 6 (15%); grade 3⫹ ⫽ 7 (17%); grade 4⫹ ⫽ 9 (22%). SEC was not present in 13 of 14 patients with in sinus rhythm. Only 1 patient with in sinus rhythm had grade 2⫹ SEC. In 19 (46%) patients with AF, dense SEC partially blurred the vision of the LA appendage (Figure 1, A). In the other 22 (54%) patients of the study group, artifacts from the limbus of the left upper pulmonary vein restricted complete visualization of the LA appendage (Figure 1, B). TEE with Echo Contrast After the application of echo contrast, none of the patients experienced any side effects. A gradual filling of the LA chamber and a consecutive filling of the LA appendage was observed in all patients. From the beginning of the appearance of echo contrast until maximal filling of the LA appendage, less than 20 heart cycles were required in all patients. However, echo contrast did not fill the LA appendage in all patients. A complete filling of the LA appendage was observed in 27 (66%) patients of the study group, 13 (32%) patients showed only a partial filling, and 1 (2%) none at all, whereas echo contrast filled the LA appendage in all patients with in sinus rhythm. The filling of the LA appendage with echo
contrast took longer in patients with AF than in those with in sinus rhythm (13 ⫾ 7 vs 9 ⫾ 5 heart cycles; P ⬍ .001). In the 19 patients with dense SEC, the use of echo contrast initially enhanced the curling blood flow pattern. Then, after maximal flooding of the LA cavity, the curling pattern was suppressed and replaced by a homogenous appearance of the echo contrast. Dense SEC in the LA appendage was completely suppressed in 12 (63%) of the 19 patients, partially suppressed in 3 (16%) patients, and in the remaining 4 (21%) patients not all (Figure 2, A). Thus, the exclusion of a LA appendage thrombus could be confirmed in 12 of the 19 patients with dense SEC by means of echo contrast application. In the 22 patients with artifacts from the limbus of the upper left pulmonary vein, complete suppression of the artifacts by the microbubbles was yielded in 13 (59%) patients and partial suppression in 3 (14%) patients. Six (27%) patients did not show any suppression at all (Figure 2, B). Consequently, LA appendage thrombi could be excluded in 13 patients by the use of echo contrast. In total, the use of echo contrast resulted in the definitive exclusion of LA thrombi in 25 of 41 patients (61%). Furthermore, in 9 of the 41 patients, the application of echo contrast resulted in the appearance of a new mass in the tip of the LA appendage that was not visualized by TEE without echo contrast. In those cases the mass was clearly delineated as a recess by the echo contrast. The masses were all mobile, distinct from the curling pattern of SEC, and distinct from the reverberations of the limbus of the pulmonary vein (Figure 3, A and B). The mean diameter and length was 1.2 cm and 0.8 cm, respectively. The patients with thrombi underwent follow up TEE after 4 weeks under continued anticoagulation therapy. In 4 patients, the repeated echo contrast study showed disappearance of the previous mass. In 2 patients without adequate anticoagulation
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Figure 2 A, Echo contrast suppressed spontaneous echo contrast (same patient as in Figure 1, A) and completely opacified left atrial appendage. B, Previous artifacts (same patient as in Figure 1, B) have been suppressed by echo contrast.
therapy, TEE without echo contrast already revealed a thrombus, located in the same position as the previously described mass. The use of echo contrast did improve the quality of the Doppler signal over the LA appendage in 19 of 41 patients (46%) and in 6 of 14 control participants (46%). However, measurement of peak emptying velocities of the LA appendage with and without echo contrast did not differ significantly (0.30 ⫾ 0.17 m/s vs 0.29 ⫾ 0.17 m/s; P ⫽ .42) in the study group. For patients with sinus rhythm, they were recorded as 0.73 ⫾ 0.15 m/s with echo contrast as 0.70 ⫾ 0.16 m/s without echo contrast (P ⫽ .13). Thromboembolic Complications after Cardioversion After exclusion of LA appendage thrombi 25 patients with AF underwent electrical cardioversion. None of them had clinical manifestations of cerebral embolism or cerebral embolism as assessed by cranial magnetic resonance imaging during a follow-up of 7 days after cardioversion.
DISCUSSION TEE-guided cardioversion of AF is an alternative approach to conventional anticoagulation. However, a potential clinical problem is the definitive exclusion of LA thrombi in patients with dense SEC or in patients with artifacts in the LA appendage. This is the first study to investigate the use of echo contrast for excluding LA appendage thrombi in patients with AF scheduled for cardioversion. The results of our study show that the application of intravenous echo contrast during the TEE study improves the capability of excluding LA thrombi in those patients. Echo Contrast for Assessing LA Appendage Morphology and Function Second-generation echo contrast agents with the ability of passing the pulmonary capillaries have been shown to improve the delineation of the left ventricular endocardial border.5 Furthermore, echo
Figure 3 A, Arrows indicate delineation of thrombus by echo contrast. B, Thrombus (arrows) is surrounded by echo contrast and is clearly delineated.
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contrast may be used to facilitate the diagnosis of left ventricular thrombi.10 Two previous studies using Albunex as a contrast agent during a TEE study demonstrated that echo contrast improves the assessment of LA appendage morphology and function.11,12 Kato et al11 reported that the application of echo contrast in patients with AF and a history of cerebral embolism may be associated with incomplete opacification of the LA appendage. Those patients with dense SEC more often had incomplete opacification of the LA appendage than those patients without SEC. Our finding of incomplete filling of the LA appendage by Optison (Mallinckrodt) in selected patients with dense SEC support the findings of Kato et al.11 In this respect our results confirm the conclusion of Kato et al11 that incomplete opacification of the LA appendage indicates a hemodynamic stasis in the LA appendage. Nevertheless, in our study 63% of patients with dense SEC showed complete opacification of the LA appendage by the use of Optison (Mallinckrodt). A potential explanation for this difference in findings is that Optison (Mallinckrodt) is a more advanced echo contrast agent with a better contrast effect and higher stability.2,13 Furthermore, we used a low mechanic index resulting in lesser destruction of the contrast agent.9 Those factors may have contributed to a better contrast effect of the used contrast agent in the LA appendage. Often the exclusion of LA appendage thrombi is difficult in patients with SEC. Our finding that a modern contrast agent may allow complete opacification of the LA appendage even in the presence of SEC is therefore of clinical importance. Complete echo contrast opacification of the LA appendage may allow excluding LA appendage thrombi with a high degree of confidence. A similar problem of reliable exclusion of LA appendage thrombi is present when artifacts occur in the cavity of the LA appendage. Those artifacts are often caused by reverberations of the limbus of the left pulmonary vein. We observed the presence of artifacts in 51% of patients in our study cohort. Interestingly, the application of echo contrast diminished these artifacts in the majority of patients. Thus, echo contrast may also be useful for excluding LA appendage thrombi when artifacts are present. Another finding of our study is that the use of echo contrast resulted in the improvement of the quality of the Doppler signal over the LA appendage in 46% of patients. This finding is in congruence with the results of Yao et al12 who showed an improvement of the Doppler signal in 63% of cases. In concordance with that study, we did not find a significant difference in peak emptying velocities of LA appendage as measured with and without echo contrast.
Journal of the American Society of Echocardiography October 2002
Echo Contrast for Delineating LA Thrombi Diagnosing LA appendage thrombi in the presence of SEC may be difficult. Furthermore, LA appendage thrombi with low echodensity may be missed by conventional echocardiography. A recent case report applying harmonic power Doppler contrast echocardiography demonstrated the depiction of an atrial thrombus that was missed by conventional TEE imaging.3 The results of our study show that the use of echo contrast in patients with dense SEC may result in the delineation of masses resembling thrombi. There are several arguments that those masses actually represent thrombi. First, the structures were mobile and had a silhouette resembling a thrombus in size and shape. Second, we observed the disappearance of those masses under continued effective anticoagulation therapy after a 4-week follow-up. On the other hand, in 2 patients with ineffective anticoagulation we observed the development of thrombi with increased echogenicity already visible with conventional TEE. Those thrombi had the same appearance as the previously diagnosed masses by contrast echocardiography. A third argument supporting the hypothesis that those phenomena are a result of thrombi and not a result of stasis is that the echo contrast agent fills around those structures (Figure 3, B). Whereas in patients with incomplete filling of the LA appendage because of decreased blood flow velocities, the pattern of the echo contrast enhancement differed. In those cases the echo contrast filled only the body of the LA appendage in a curtain like manner. Thanigaraj et al10 reported similar findings with respect to left ventricular thrombi. In their study, echo contrast smoothly delineated the left ventricular endocardium in the absence of thrombi. In the presence of thrombi this delineation became irregular. Furthermore, they found no case where contrast enhancement mimicked or masqueraded a left ventricular thrombus.10 Echo Contrast for the Exclusion of LA Thrombi by TEE Before Cardioversion This is the first study to evaluate the use of echo contrast for excluding LA thrombi in patients scheduled for cardioversion. The results of our study show that the application of echo contrast facilitates the exclusion of LA thrombi in patients with dense SEC or in patients with artifacts in the LA appendage. Artifacts in the LA appendage as produced by reverberations of the limbus of the left pulmonary vein are a potential clinical problem and may mimic LA appendage thrombi, resulting in the false positive diagnosis of an atrial thrombus. As a consequence those patients may be excluded from cardioversion. Our results show that the application of echo contrast reduces artifacts because of reverberations in
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the majority of patients. Thus, a reliable exclusion of LA appendage thrombi is ensured in those cases. SEC represents a low-flow phenomenon in the LA appendage.14 In patients with dense SEC the tip of the LA appendage often can not be completely visualized and an exclusion of a thrombus is difficult. Our findings show that a stable contrast agent may allow for delayed, but complete opacification of the LA appendage. Thus, the exclusion of a thrombus may be confirmed. In this respect it is interesting that none of our patients with exclusion of LA appendage thrombi by means of echo contrast had thromboembolic complications after cardioversion of AF.
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3.
4.
5. 6.
Clinical Implications The finding of our study that a second-generation echo contrast agent may enhance the exclusion or identification of LA appendage thrombi by means of TEE in patients with suboptimal conventional TEE examinations provides a valuable contribution to more comprehensive treatment decision in those patients. This fact is underlined by our finding that none of the patients who underwent cardioversion of AF had thromboembolic complications afterward.
7. 8.
9.
Limitations 10.
A potential limitation of our study is that we could not use anatomical validation for excluding or identifying LA appendage thrombi. Furthermore, contrast echocardiography does not allow for the differentiation of small thrombi from trabeculation. Thus, definitive proof of the presence of thrombi as diagnosed by echo contrast TEE is not possible. However, we did not observe thromboembolic complications after echo contrast TEE-guided exclusion of LA thrombi. REFERENCES 1. Klein AL, Grimm RA, Black IW, Leung DY, Chung MK, Vaughn SE, et al. Cardioversion guided by transesophageal echocardiography, the ACUTE Pilot Study; a randomized, controlled trial: assessment of cardioversion using transesophageal echocardiography. Ann Intern Med 1997;126:200-9. 2. Cohen JL, Cheirif J, Segar DS, Gillam LD, Gottdiener JS,
11.
12.
13.
14.
Hausnerova E, et al. Improved left ventricular endocardial border delineation and opacification with Optison(FS069), a new echocardiographic contrast agent: results of a phase III multicenter trial. J Am Coll Cardiol 1998;32:746-52. Bednarz JE, Spencer KT, Weinert L, Sugeng L, Mor-Avi V, Lang RM. Identification of cardiac masses and abnormal blood flow patterns with harmonic power Doppler contrast echocardiography. J Am Soc Echocardiogr 1999;12:871-5. Omran H, Jung W, Rabahieh R, Wirtz P, Becher H, Illien S, et al. Imaging of thrombi and assessment of left atrial appendage function: a prospective study comparing transthoracic and transoesophageal echocardiography. Heart 1999;81:192-8. Clark LN, Dittrich HC. Cardiac imaging using Optison. Am J Cardiol 2000;86:14-8G. Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp RL, et al. Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Twodimensional Echocardiography. Circulation 1980;62:212-5 Weyman AE. Principles and practice of echocardiography. 2nd ed. Philadelphia: Lea & Febiger; 1994. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23:961-9. Wible JH Jr, Wojdyla JK, Hughes MS, Brandenburger GH. Effects of transducer frequency and output power on the ultrasonographic contrast produced by Optison using fundamental and harmonic imaging techniques. J Ultrasound Med 1999;18:753-62. Thanigaraj S, Schechtman KB, Perez JE. Improved echocardiographic delineation of left ventricular thrombus with the use of intravenous second-generation contrast image enhancement. J Am Soc Echocardiogr 1999;12:1022-6. Kato H, Nakanishi M, Maekawa N, Ohnishi T, Yamamoto M. Evaluation of left atrial appendage stasis in patients with atrial fibrillation using transesophageal echocardiography with an intravenous albumin-contrast agent. Am J Cardiol 1996;78: 365-9. Yao SS, Ilercil A, Meisner JS, Strom JA, Shirani J. Improved Doppler echocardiographic assessment of the left atrial appendage by peripheral vein injection of sonicated albumin microbubbles. Am Heart J 1997;133:400-5. Skyba DM, Camarano G, Goodman NC, Price RJ, Skalak TC, Kaul S. Hemodynamic characteristics, myocardial kinetics and microvascular rheology of FS-069, a second-generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection. J Am Coll Cardiol 1996;28:1292-300. Black IW. Spontaneous echo contrast: where there’s smoke there’s fire. Echocardiography 2000;17:373-82.