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Effect of Elevated Left Ventricular Diastolic Filling Pressure on the Frequency of Left Atrial Appendage Thrombus in Patients With Nonvalvular Atrial Fibrillation
Effect of Elevated Left Ventricular Diastolic Filling Pressure on the Frequency of Left Atrial Appendage Thrombus in Patients With Nonvalvular Atrial Fibrillation Katsuomi Iwakura, MD*, Atsushi Okamura, MD, Yasushi Koyama, MD, Motoo Date, MD, Yoshiharu Higuchi, MD, Koichi Inoue, MD, Ryusuke Kimura, MD, Hiroyuki Nagai, MD, Yuko Toyoshima, MD, Makito Ozawa, MD, Norihisa Ito, MD, Masahiko Shibuya, MD, Shigemiki Omiya, MD, Takashi Takagi, MD, Daisuke Morisawa, MD, and Kenshi Fujii, MD We investigated the relation between left ventricular diastolic dysfunction and left atrial appendage (LAA) thrombus in patients with atrial fibrillation (AF). We performed transesophageal echocardiography to examine LAA thrombus or spontaneous echo contrast (SEC) and to measure LAA emptying flow velocity in consecutive 376 patients with AF. We estimated diastolic filling pressure as the ratio of early transmitral flow velocity (E) to mitral annular velocity (e=) on transthoracic echocardiogram. E/e= ratio in 28 patients (7.4%) with LAA thrombi was higher than that in patients without thrombus (18.3 ⴞ 9.3 vs 11.4 ⴞ 5.9, p <0.0001). The fourth quartile of E/e= (>13.6) consisted of 19 patients with thrombi and had a higher prevalence of thrombi than the others (p <0.0001). Multivariate regression analysis selected E/e= >13 as an independent predictor of LAA thrombus with an odds ratio of 3.50 (1.22 to 10.61) in addition to LA dimension and ejection fraction. Increased quartile of E/e= was negatively associated with LAA flow velocity and positively with rate of SEC. In conclusion, increased diastolic filling pressure is associated with a higher rate of LAA thrombus in AF, partly through blood stasis or impaired LAA function. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:417– 422) Left ventricular (LV) diastolic dysfunction is a common feature of risk factors for stroke in patients with atrial fibrillation (AF), but its relation to left atrial appendage (LAA) thrombus is not well elucidated. The ratio of early transmitral flow velocity (E) to mitral annulus velocity during diastole (e=) correlates closely to LV diastolic filling pressures.1–3 It is the most reliable echocardiographic index to detect LV diastolic dysfunction4 even in AF.5,6 In the present study, we investigated the relation between E/e= and LAA thrombus in patients with AF. We also investigated the relation between E/e= and LA spontaneous echo contrast (SEC) and LAA emptying flow velocity to clarify the mechanism that exacerbates LAA thrombus formation. Methods We enrolled consecutive 376 patients with nonrheumatic, paroxysmals or persistent AF from January 2006 to December 2007 who underwent transthoracic echocardiography and transesophageal echocardiography within a 30-day period. We excluded patients with mitral stenosis or previous mitral valve surgery. We also excluded patients with biventricular pacemaker or with New York
Division of Cardiology, Sakurabashi Watanabe Hospital, Osaka, Japan. Manuscript received August 3, 2010; revised manuscript received and accepted September 24, 2010. *Corresponding author: Tel: 81-6-6341-8651; fax: 81-6-6341-0785. E-mail address: [email protected] (K. Iwakura). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.09.042
Heart Association class IV heart failure because E/e= might not properly estimate LV filling pressure in these patients.7 We confirmed presence of AF in each patient by ⱖ1 AF episode documented with electrocardiography. If a patient underwent multiple transthoracic or transesophageal echocardiographic examinations, we chose the earliest examination as an index study. We reviewed medical records of all patients to determine clinical features including age, gender, history of hypertension, diabetes, stroke, structural heart diseases, congestive heart failure, and state of anticoagulant therapy at time of transesophageal echocardiography. Presence of heart failure was determined based on medical records, patients’ symptoms, physical examinations, or medical tests. We calculated a CHADS2 score to evaluate the risk of cardiogenic stroke.8 The study protocol was approved by the hospital’s ethics committee. One investigator obtained informed consent from each patient before transthoracic or transesophageal echocardiography. We performed transesophageal echocardiography using a SSD-6500 system (Aloka, Mitaka, Tokyo, Japan) equipped with a 5.0-MHz monoplane transesophageal probe. LAA was viewed in midesophageal short-axis and 2-chamber images. LAA thrombus was defined as a well-circumscribed, echocardiographically reflective mass that was of different texture than the atrial wall and that had a uniform consistency.9,10 SEC was defined as a dynamic smoke-like signal that swirled slowly in a circular pattern within the left atrium.11,12 LAA flow velocity profiles were obtained by pulse-wave Doppler www.ajconline.org
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Table 1 Clinical characteristics of study patients Variables
Age (years) Men/women Paroxysmal/persistent atrial fibrillation Atrial fibrillation during transesophageal echocardiography Structural heart disease Anticoagulation therapy International normalized ratio of prothrombin time* Heart failure Hypertension Diabetes mellitus Previous stroke CHADS2 score
All Patients (n ⫽ 375)
LAA Thrombus
p Value
No (n ⫽ 347)
Yes (n ⫽ 28)
64 ⫾ 11 293/80 246/130 197 (52.4%)
63 ⫾ 11 269/76 236/112 175 (50.3%)
68 ⫾ 10 24/4 10/18 22 (78.6%)
0.03 0.34 0.0006 0.004
95 (25.3) 218 (58.1%) 1.9 ⫾ 0.7 206 (54.7%) 177 (47.1%) 59 (15.7%) 38 (10.1%) 1.5 ⫾ 1.3
79 (22.8) 202 (58.1%) 2.2 ⫾ 0.9 182 (52.3%) 161 (46.3%) 52 (14.9%) 32 (9.2%) 1.5 ⫾ 1.2
16 (57.1) 16 (57.1%) 1.9 ⫾ 0.5 24 (85.7%) 16 (57.1%) 7 (25.0%) 6 (21.4%) 2.4 ⫾ 1.4
⬍0.0001 0.93 0.08 0.0006 0.27 0.16 0.04 0.0001
Values are numbers of patients (percentages) or means ⫾ SDs. * International normalized ratio of prothrombin time was an average value in patients receiving warfarin.
Table 2 Transthoracic and transesophageal echocardiographic parameters in study patients Variables
Left atrial diameter (cm) Left ventricular end-diastolic diameter (cm) Ejection fraction (%) Relative wall thickness Left ventricular mass index (g/m2) Mitral regurgitation at least moderate grade Early transmitral flow velocity/mitral annular velocity (E/e=) Spontaneous echo contrast Left atrial appendage flow velocity (cm/s)
All Patients (n ⫽ 375)
3.8 ⫾ 0.6 49 ⫾ 6 61 ⫾ 14 0.43 ⫾ 0.09 120 ⫾ 39 126 (33.5%) 11.9 ⫾ 6.4 120 (31.9%) 44.0 ⫾ 20.0
LAA Thrombus No (n ⫽ 347)
Yes (n ⫽ 28)
3.7 ⫾ 0.6 49 ⫾ 6 62 ⫾ 13 0.43 ⫾ 0.08 118 ⫾ 37 110 (31.6%) 11.4 ⫾ 5.9 96 (27.6%) 44.8 ⫾ 20.1
4.4 ⫾ 0.8 54 ⫾ 9 48 ⫾ 20 0.42 ⫾ 0.09 153 ⫾ 45 16 (57.1%) 18.3 ⫾ 9.3 24 (85.7%) 30.7 ⫾ 12.4
p Value
⬍0.0001 ⬍0.0001 0.0009 0.51 ⬍0.0001 0.006 ⬍0.0001 ⬍0.0001 0.002
Values are means ⫾ SDs or numbers of patients (percentages).
echocardiography with sample volume placed at the LAA orifice. LAA peak emptying velocities were averaged with each RR interval over ⱖ5 consecutive cardiac cycles.13,14 We performed transthoracic echocardiographic examination using a SONOS 7500 or iE-33 system (Philips Healthcare, Andover, Massachusetts). We recorded tissue Doppler images from the apical 4-chamber view and measured septal e= (centimeters per second) on the pulse-wave Doppler spectrum as an average of 5 consecutive beats. We measured transmitral E (centimeters per second) as an average of 5 consecutive cardiac cycles and calculated an E/e= ratio. We also measured LA diameter, LV end-diastolic dimension, and LV ejection fraction. LV mass (grams) was calculated as 0.80 ⫻ (1.04 ⫻ [{septal wall thickness in diastole ⫹ LV end-diastolic dimension ⫹ posterior wall thickness in diastole}3 ⫺ LV end-diastolic dimension3]) ⫹ 0.6 and indexed to body surface area as LV mass index.15 Relative wall thickness was calculated as 2 ⫻ (posterior wall thickness in diastole)/LV end-diastolic dimension.15 Mitral regurgitation was qualitatively graded as none, mild, moderate, or severe based on regurgitant jet area and spatial distribution of regurgitant flow.
All continuous variables are expressed as mean ⫾ SD and were compared by 1-way analysis of variance. Significance of difference was calculated with the Tukey Honestly Significant Difference test for factor analysis. Categorical variables were compared with Fisher’s exact test. We performed logistic multivariate regression analysis to determine clinical and transthoracic echocardiographic factors for predicting LAA thrombus formation; clinical factors used for analysis were age, gender, history of hypertension, diabetes mellitus, previous stroke, congestive heart failure, structural heart disease, type of AF (paroxysmal or persistent), and state of anticoagulant therapy. Echocardiographic parameters were LA diameter, LV end-diastolic dimension, ejection fraction, LV mass index, relative wall thickness, presence of at least moderate mitral regurgitation, and E/e= ⱖ13. We performed receiver operator curve analysis to determine the optimal cut-off value of E/e= for predicting LAA thrombus. Differences were considered statistically significant at a p value ⬍0.05 (2-sided). JMP 5.0.1 (SAS Institute, Cary, North Carolina) was used for statistical analysis.
Arrhythmias and Conduction Disturbances/Diastolic Filling Pressure and LA Thrombus
Figure 1. Patients were categorized into 4 groups based on quartile (Q) of the ratio of early transmitral flow velocity to mitral annular velocity (ratio ranges). Incidence of left atrial appendage thrombus (vertical bar) in the fourth quartile of the ratio of early transmitral flow velocity to mitral annular velocity (E/e=) was significantly (p ⬍0.0001) higher than those in the other 3 groups.
Results LAA thrombi were observed in 28 patients (7.4%) on transesophageal echocardiogram. Patients with LAA thrombi were significantly older and had higher prevalence of persistent AF and of structural heart disease than those without thrombus (Table 1). More patients with thrombi were in AF at transesophageal echocardiography than were those without thrombus. Numbers of patients receiving warfarin were comparable between those with and without thrombi. International normalized ratio of prothrombin time showed no differences between the 2 subsets of those receiving warfarin. Incidences of hypertension and diabetes showed no differences between the 2 subsets. Previous stroke and heart failure were more frequently observed in patients with LAA thrombi. Therefore, patients with thrombi had significantly higher CHADS2 scores than those without thrombus. Transthoracic echocardiography was performed before or after transesophageal echocardiography with median of 6-day interval (25% to 75% quartile, 3 to 9 days). E/e= was significantly higher in patients with LAA thrombi than in those without thrombus (18.3 ⫾ 9.3 vs 11.4 ⫾ 5.9, p ⬍0.0001). Patients with LAA thrombi also had larger LA diameters and LV end-diastolic dimension, lower ejection fraction, and higher prevalence of at least moderate mitral regurgitation than those without thrombus (Table 2). There were no significant differences in relative wall thickness and LV mass index. We divided the study patients into 4 groups based on quartile of E/e=. E/e= ⬎15, a widely used estimate of increased LV filling pressure,2,3 was observed in 75 of 94 patients in the fourth quartile (E/e= ⬎13.6). Nineteen of 28 patients with LAA thrombi were in quartile 4, and quartile 4 had more patients with LAA thrombi than the other 3 groups (p ⬍0.0001; Figure 1). However, only 19 of 94 patients (20.2%) in quartile 4 had LAA thrombi. Receiver operator curve analysis demonstrated that 12.8 was the optimal cut-off value of E/e= for predicting LAA
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Figure 2. Receiver operator curve analysis indicated that 12.8 was the optimal cut-off value of the ratio of transmitral early mitral valve flow velocity to mitral annular velocity for predicting left atrial appendage thrombi (area under the curve 0.77). Table 3 Predictors of left atrial appendage thrombus among clinical and transthoracic echocardiographic parameters
Ejection fraction Early transmitral flow velocity/mitral annular velocity ⱖ13 Left atrial diameter Persistent atrial fibrillation Left ventricular end-diastolic dimension Heart failure Mitral regurgitation at least moderate grade Age Gender Left ventricular mass index Relative wall thickness Anticoagulation therapy Atrial fibrillation during transesophageal echocardiography Diabetes mellitus Structural heart disease Previous stroke Hypertension
Wald Chisquare
p Value
7.97 5.26
0.005 0.02
4.32 3.06 2.07 2.17 2.09 1.01 0.75 0.62 0.42 0.51 0.72
0.04 0.08 0.15 0.14 0.15 0.32 0.39 0.43 0.52 0.48 0.70
0.18 0.06 0.06 0.007
0.67 0.80 0.80 0.93
thrombus (area under the curve 0.77; Figure 2). Based on an equation by Nagueh et al,1 E/e= equal to 12.8 corresponds to 20 mm Hg of LV filling pressure. E/e= ⬎12.8 predicted presence of LAA thrombus with 75.0% sensitivity and 74.4% specificity. Using clinical and transthoracic echocardiographic parameters, we performed logistic multivariate analysis to determine the predictors for LAA thrombi. We used E/e= ⱖ13 as a factor for analysis. LA diameter, LV ejection fraction, and E/e= ⱖ13 were selected as significant predictors for LAA thrombus among clinical and echocardiographic parameters (Table 3). E/e= ⱖ13 had an odds ratio of 3.50 (95% confidence interval 1.22 to 10.61) for LAA thrombus. We investigated relations between E/e= and LAA emptying flow velocity. Patients with LAA thrombi had lower
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Figure 3. (Left) Ratio of early transmitral flow velocity to mitral annular velocity (E/e=) was weakly but significantly correlated with left atrial appendage flow velocity (r ⫽ 0.2, p ⫽ 0.0002); 95% confidence intervals (dashed lines) are shown for the regression line. (Right) When study patients were categorized into 4 groups based on quartile of the ratio of early transmitral flow velocity to mitral annular velocity, an increased ratio quartile was associated with lower left atrial appendage blood flow velocity (p ⫽ 0.0005 by analysis of variance). Quartile 4 had significantly lower velocity than quartiles 1 and 2, whereas no significant differences were observed among quartiles 1, 2, and 3. *p ⫽ 0.03; **p ⫽ 0.0002 versus quartile 4. Abbreviation as in Figure 1.
(24 patients, 20%, vs 4 patients, 1.6%, p ⬍0.0001). They also had significant larger LA dimension (4.2 ⫾ 0.6 vs 3.6 ⫾ 0.5 cm, p ⬍0.0001). Patients with SEC had higher E/e= than those without SEC (15.2 ⫾ 7.9 vs 10.4 ⫾ 4.9, p ⬍0.0001). Increased E/e= quartile was associated with higher prevalence of SEC (p ⬍0.0001; Figure 4). Discussion
Figure 4. Prevalence of spontaneous echo contrast in study patients based on ratio of early transmitral flow velocity to mitral annular velocity (ratio ranges). Increased quartile of the ratio of early transmitral flow velocity to mitral annular velocity was associated with higher rates of spontaneous echo contrast (p ⬍0.0001). Abbreviation as in Figure 1.
LAA flow velocity than those without thrombus (30.7 ⫾ 12.4 vs 44.8 ⫾ 20.1 cm/s, p ⫽ 0.002). E/e= ratio was weakly but significantly correlated with LAA flow velocity (r ⫽ 0.2, p ⫽ 0.0002). Increased E/e= quartile was significantly associated with decreased LAA flow velocity (p ⫽ 0.0005 by analysis of variance). Quartile 4 had significantly lower velocity than quartiles 1 and 2 (quartile 4 vs 1 37.2 ⫾ 17.5 vs 49.7 ⫾ 22.8 cm/s, p ⫽ 0.0002, vs quartile 2 45.3 ⫾ 19.2 cm/s, p ⫽ 0.03, vs quartile 3 44.7 ⫾ 18.7 cm/s, p ⫽ 0.13), although there were no significant differences among quartiles 1, 2, and 3 (Figure 3). LAA flow velocity was also weakly correlated with LA dimension (r ⫽ 0.36, p ⬍0.0001). SEC was observed in 24 patients (85.7%) with LAA thrombi and in only 96 patients (27.6%, p ⬍0.0001) without thrombi (Table 2). Patients with SEC had significantly higher incidences of LAA thrombi than those without SEC
LAA thrombi were observed on transesophageal echocardiogram in 28 of 376 patients (7.4%) with AF, and patients with LAA thrombi had higher E/e= than those without thrombus. Most patients with thrombi were in quartile 4 of E/e=, and E/e= equal to 12.8 (corresponding to about 20 mm Hg of filling pressure) was the optimal cut-off point for predicting LAA thrombus. Multivariate logistic analysis selected LA diameter, LV ejection fraction, and E/e= ⱖ13 as significant predictors for LAA thrombus among clinical and echocardiographic parameters. Odds ratio of E/e= ⱖ13 for LAA thrombi was 3.50 (95% confidence interval 1.22 to 10.61). E/e= was associated with LAA flow velocity and with incidence of SEC, suggesting that LV diastolic dysfunction could contribute to LAA thrombosis, at least partly, through impairment of LAA emptying function and blood stasis within the left atrium. LAA thrombi were more frequently observed in quartile 4 of E/e= and no differences were observed among the other 3 quartiles. Thus, LAA thrombus formation is related to increased LV filling pressure, although its increase within normal range might not exacerbate thrombus formation. LA function is preserved at the early phase of LV diastolic dysfunction, but further increase in LV filling pressure increases workload on the LA myocardium and causes LA dysfunction.16 LAA blood flow velocity was decreased in quartile 4 of E/e= compared to that in other quartiles, although the correlation between E/e= and LAA flow velocity was very weak, indicating that LAA function was attenuated by increased LA filling pressure. Previous studies also demonstrated that increased LV diastolic filling pressure atten-
Arrhythmias and Conduction Disturbances/Diastolic Filling Pressure and LA Thrombus
uates LAA blood flow velocity in AF17 and in sinus rhythm.18,19 In contrast, incidence of SEC was increased as was quartile of E/e=, indicating that blood stasis within the left atrium could be exacerbated by an increase in diastolic filling pressure even within normal range. Prevalence of LA thrombus in AF is associated with density grade of SEC.20 Higher diastolic filling pressure might be related to a higher grade of SEC, although the grade of SEC was not evaluated in the present study. Multivariate analysis demonstrated that LA dimension and E/e= ⱖ13 were independent factors for LAA thrombus. However, increased filling pressure could exert its effects through secondary changes in LA size. An enlarged left atrium is also associated with higher incidences of SEC21 and with LAA dysfunction,22 which was also demonstrated in the present study. LA dilatation in patients with nonvalvular chronic AF is associated with an increase in coagulate factors23 and with endothelial dysfunction.24 Measurement of E/e= might have only limited ability to predict LA thrombus in AF. In contrast, the present results suggest the possibility that treatment of diastolic dysfunction could decrease the risk of stroke in the high-risk AF population. Increased diastolic filling pressure is reported to be associated with all-cause mortality in patients with nonvalvular AF.25 A prospective study to investigate the effects of treatment of diastolic dysfunction on thrombosis in AF is expected. Because the present study was retrospective, the results should be interpreted carefully. E/e= measured during AF could be less accurate than in the sinus rhythm, although it might be somehow correlated with diastolic filling pressure. Prevalence of heart failure might be higher than in the general AF population,26 although a similar prevalence was reported in another large-scale trial of AF.27 One explanation was that the present study was conducted in a tertiary hospital. We might have overestimated incidence of heart failure because of a difficulty in differentiating symptoms due to heart failure from those due to AF. The number of patients receiving warfarin might be smaller than expected. A substantial proportion of patients underwent transesophageal echocardiography just before catheter ablation, and warfarin was temporarily stopped. Modest CHADS2 scores in the present patients (1.5 ⫾ 1.3) could be another reason for the lower rate of warfarin treatment. International normalized ratio of prothrombin time in patients receiving warfarin (1.9 ⫾ 0.7) might be lower than the optimal therapeutic range, and this was because a range from 1.6 to 2.1 is recommended for elderly patients with AF in Japan.28 We did not determine frequency and/or duration of AF episodes in patients with paroxysmal AF, although increased LV filling pressure might increase the number of paroxysmal AF episodes.29 In conclusion, increased diastolic filling pressure, estimated as E/e=, could be associated with higher frequency of LAA thrombus in patients with AF. Blood stasis or impaired LAA function could partly contribute to an increase in LAA thrombosis.
2.
3.
4.
5.
6.
7.
8.
9.
10. 11. 12.
13. 14.
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sinus tachycardia. A new application of tissue Doppler imaging. Circulation 1998;98:1644 –1650. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 2000;102:1788 –1794. Ha JW, Oh JK, Ling LH, Nishimura RA, Seward JB, Tajik AJ. Annulus paradoxus: transmitral flow velocity to mitral annular velocity ratio is inversely proportional to pulmonary capillary wedge pressure in patients with constrictive pericarditis. Circulation 2001;104: 976 –978. Kasner M, Westermann D, Steendijk P, Gaub R, Wilkenshoff U, Weitmann K, Hoffmann W, Poller W, Schultheiss HP, Pauschinger M, Tschope C. Utility of Doppler echocardiography and tissue Doppler imaging in the estimation of diastolic function in heart failure with normal ejection fraction: a comparative Doppler-conductance catheterization study. Circulation 2007;116:637– 647. Sohn DW, Song JM, Zo JH, Chai IH, Kim HS, Chun HG, Kim HC. Mitral annulus velocity in the evaluation of left ventricular diastolic function in atrial fibrillation. J Am Soc Echocardiogr 1999;12:927– 931. Watanabe T, Iwai-Takano M, Oikawa M, Yamaki T, Yaoita H, Maruyama Y. Optimal noninvasive assessment of diastolic heart failure in patients with atrial fibrillation: comparison of tissue Doppler echocardiography, left atrium size, and brain natriuretic peptide. J Am Soc Echocardiogr 2008;21:689 – 696. Mullens W, Borowski AG, Curtin RJ, Thomas JD, Tang WH. Tissue Doppler imaging in the estimation of intracardiac filling pressure in decompensated patients with advanced systolic heart failure. Circulation 2009;119:62–70. Gage BF, van Walraven C, Pearce L, Hart RG, Koudstaal PJ, Boode BS, Petersen P. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation 2004;110:2287–2292. Manning WJ, Weintraub RM, Waksmonski CA, Haering JM, Rooney PS, Maslow AD, Johnson RG, Douglas PS. Accuracy of transesophageal echocardiography for identifying left atrial thrombi. A prospective, intraoperative study. Ann Intern Med 1995;123:817– 822. Seward JB, Khandheria BK, Oh JK, Freeman WK, Tajik AJ. Critical appraisal of transesophageal echocardiography: limitations, pitfalls, and complications. J Am Soc Echocardiogr 1992;5:288 –305. Castello R, Pearson AC, Labovitz AJ. Prevalence and clinical implications of atrial spontaneous contrast in patients undergoing transesophageal echocardiography. Am J Cardiol 1990;65:1149 –1153. Chimowitz MI, DeGeorgia MA, Poole RM, Hepner A, Armstrong WM. Left atrial spontaneous echo contrast is highly associated with previous stroke in patients with atrial fibrillation or mitral stenosis. Stroke 1993;24:1015–1019. Tsai LM, Chao TH, Chen JH. Association of follow-up change of left atrial appendage blood flow velocity with spontaneous echo contrast in nonrheumatic atrial fibrillation. Chest 2000;117:309 –313. Palinkas A, Antonielli E, Picano E, Pizzuti A, Varga A, Nyuzo B, Alegret JM, Bonzano A, Tanga M, Coppolino A, Forster T, Baralis G, Delnevo F, Csanady M. Clinical value of left atrial appendage flow velocity for predicting of cardioversion success in patients with nonvalvular atrial fibrillation. Eur Heart J 2001;22:2201–2208. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440 –1463. Kono T, Sabbah HN, Rosman H, Alam M, Stein PD, Goldstein S. Left atrial contribution to ventricular filling during the course of evolving heart failure. Circulation 1992;86:1317–1322. Lin JM, Hsu KL, Hwang JJ, Tseng YZ. Influence of left ventricular diastole on left atrial appendage blood flow in patients with nonrheumatic atrial fibrillation. Cardiology 1997;88:563–568. Hoit BD, Shao Y, Gabel M. Influence of acutely altered loading conditions on left atrial appendage flow velocities. J Am Coll Cardiol 1994;24:1117–1123.
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19. Tabata T, Oki T, Fukuda N, Iuchi A, Manabe K, Kageji Y, Sasaki M, Yamada H, Ito S. Influence of left atrial pressure on left atrial appendage flow velocity patterns in patients in sinus rhythm. J Am Soc Echocardiogr 1996;9:857– 864. 20. 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;23:961–969. 21. Sadanandan S, Sherrid MV. Clinical and echocardiographic characteristics of left atrial spontaneous echo contrast in sinus rhythm. J Am Coll Cardiol 2000;35:1932–1938. 22. Goldman ME, Pearce LA, Hart RG, Zabalgoitia M, Asinger RW, Safford R, Halperin JL. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (the Stroke Prevention in Atrial Fibrillation [SPAF-III] study). J Am Soc Echocardiogr] 1999;12:1080 –1087. 23. Mondillo S, Sabatini L, Agricola E, Ammaturo T, Guerrini F, Barbati R, Pastore M, Fineschi D, Nami R. Correlation between left atrial size, prothrombotic state and markers of endothelial dysfunction in patients with lone chronic nonrheumatic atrial fibrillation. Int J Cardiol 2000; 75:227–232. 24. Cai H, Li Z, Goette A, Mera F, Honeycutt C, Feterik K, Wilcox JN, Dudley SC, Jr., Harrison DG, Langberg JJ. Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke. Circulation 2002;106:2854 –2858.
25. Okura H, Takada Y, Kubo T, Iwata K, Mizoguchi S, Taguchi H, Toda I, Yoshikawa J, Yoshida K. Tissue Doppler-derived index of left ventricular filling pressure, E/E=, predicts survival of patients with non-valvular atrial fibrillation. Heart 2006;92:1248 –1252. 26. Nieuwlaat R, Capucci A, Camm AJ, Olsson SB, Andresen D, Davies DW, Cobbe S, Breithardt G, Le Heuzey JY, Prins MH, Levy S, Crijns HJ. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005;26:2422–2434. 27. Cleland JG, Shelton R, Nikitin N, Ford S, Frison L, Grind M. Prevalence of markers of heart failure in patients with atrial fibrillation and the effects of ximelagatran compared to warfarin on the incidence of morbid and fatal events: a report from the SPORTIF III and V trials. Eur J Heart Fail 2007;9:730 –739. 28. Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group. Stroke 2000;31:817– 821. 29. Tsang TS, Gersh BJ, Appleton CP, Tajik AJ, Barnes ME, Bailey KR, Oh JK, Leibson C, Montgomery SC, Seward JB. Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol 2002;40:1636 –1644.
Division of Cardiology, Sakurabashi Watanabe Hospital, Osaka, Japan. Manuscript received August 3, 2010; revised manuscript received and accepted September 24, 2010. *Corresponding author: Tel: 81-6-6341-8651; fax: 81-6-6341-0785. E-mail address: [email protected] (K. Iwakura). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.09.042
Heart Association class IV heart failure because E/e= might not properly estimate LV filling pressure in these patients.7 We confirmed presence of AF in each patient by ⱖ1 AF episode documented with electrocardiography. If a patient underwent multiple transthoracic or transesophageal echocardiographic examinations, we chose the earliest examination as an index study. We reviewed medical records of all patients to determine clinical features including age, gender, history of hypertension, diabetes, stroke, structural heart diseases, congestive heart failure, and state of anticoagulant therapy at time of transesophageal echocardiography. Presence of heart failure was determined based on medical records, patients’ symptoms, physical examinations, or medical tests. We calculated a CHADS2 score to evaluate the risk of cardiogenic stroke.8 The study protocol was approved by the hospital’s ethics committee. One investigator obtained informed consent from each patient before transthoracic or transesophageal echocardiography. We performed transesophageal echocardiography using a SSD-6500 system (Aloka, Mitaka, Tokyo, Japan) equipped with a 5.0-MHz monoplane transesophageal probe. LAA was viewed in midesophageal short-axis and 2-chamber images. LAA thrombus was defined as a well-circumscribed, echocardiographically reflective mass that was of different texture than the atrial wall and that had a uniform consistency.9,10 SEC was defined as a dynamic smoke-like signal that swirled slowly in a circular pattern within the left atrium.11,12 LAA flow velocity profiles were obtained by pulse-wave Doppler www.ajconline.org
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Table 1 Clinical characteristics of study patients Variables
Age (years) Men/women Paroxysmal/persistent atrial fibrillation Atrial fibrillation during transesophageal echocardiography Structural heart disease Anticoagulation therapy International normalized ratio of prothrombin time* Heart failure Hypertension Diabetes mellitus Previous stroke CHADS2 score
All Patients (n ⫽ 375)
LAA Thrombus
p Value
No (n ⫽ 347)
Yes (n ⫽ 28)
64 ⫾ 11 293/80 246/130 197 (52.4%)
63 ⫾ 11 269/76 236/112 175 (50.3%)
68 ⫾ 10 24/4 10/18 22 (78.6%)
0.03 0.34 0.0006 0.004
95 (25.3) 218 (58.1%) 1.9 ⫾ 0.7 206 (54.7%) 177 (47.1%) 59 (15.7%) 38 (10.1%) 1.5 ⫾ 1.3
79 (22.8) 202 (58.1%) 2.2 ⫾ 0.9 182 (52.3%) 161 (46.3%) 52 (14.9%) 32 (9.2%) 1.5 ⫾ 1.2
16 (57.1) 16 (57.1%) 1.9 ⫾ 0.5 24 (85.7%) 16 (57.1%) 7 (25.0%) 6 (21.4%) 2.4 ⫾ 1.4
⬍0.0001 0.93 0.08 0.0006 0.27 0.16 0.04 0.0001
Values are numbers of patients (percentages) or means ⫾ SDs. * International normalized ratio of prothrombin time was an average value in patients receiving warfarin.
Table 2 Transthoracic and transesophageal echocardiographic parameters in study patients Variables
Left atrial diameter (cm) Left ventricular end-diastolic diameter (cm) Ejection fraction (%) Relative wall thickness Left ventricular mass index (g/m2) Mitral regurgitation at least moderate grade Early transmitral flow velocity/mitral annular velocity (E/e=) Spontaneous echo contrast Left atrial appendage flow velocity (cm/s)
All Patients (n ⫽ 375)
3.8 ⫾ 0.6 49 ⫾ 6 61 ⫾ 14 0.43 ⫾ 0.09 120 ⫾ 39 126 (33.5%) 11.9 ⫾ 6.4 120 (31.9%) 44.0 ⫾ 20.0
LAA Thrombus No (n ⫽ 347)
Yes (n ⫽ 28)
3.7 ⫾ 0.6 49 ⫾ 6 62 ⫾ 13 0.43 ⫾ 0.08 118 ⫾ 37 110 (31.6%) 11.4 ⫾ 5.9 96 (27.6%) 44.8 ⫾ 20.1
4.4 ⫾ 0.8 54 ⫾ 9 48 ⫾ 20 0.42 ⫾ 0.09 153 ⫾ 45 16 (57.1%) 18.3 ⫾ 9.3 24 (85.7%) 30.7 ⫾ 12.4
p Value
⬍0.0001 ⬍0.0001 0.0009 0.51 ⬍0.0001 0.006 ⬍0.0001 ⬍0.0001 0.002
Values are means ⫾ SDs or numbers of patients (percentages).
echocardiography with sample volume placed at the LAA orifice. LAA peak emptying velocities were averaged with each RR interval over ⱖ5 consecutive cardiac cycles.13,14 We performed transthoracic echocardiographic examination using a SONOS 7500 or iE-33 system (Philips Healthcare, Andover, Massachusetts). We recorded tissue Doppler images from the apical 4-chamber view and measured septal e= (centimeters per second) on the pulse-wave Doppler spectrum as an average of 5 consecutive beats. We measured transmitral E (centimeters per second) as an average of 5 consecutive cardiac cycles and calculated an E/e= ratio. We also measured LA diameter, LV end-diastolic dimension, and LV ejection fraction. LV mass (grams) was calculated as 0.80 ⫻ (1.04 ⫻ [{septal wall thickness in diastole ⫹ LV end-diastolic dimension ⫹ posterior wall thickness in diastole}3 ⫺ LV end-diastolic dimension3]) ⫹ 0.6 and indexed to body surface area as LV mass index.15 Relative wall thickness was calculated as 2 ⫻ (posterior wall thickness in diastole)/LV end-diastolic dimension.15 Mitral regurgitation was qualitatively graded as none, mild, moderate, or severe based on regurgitant jet area and spatial distribution of regurgitant flow.
All continuous variables are expressed as mean ⫾ SD and were compared by 1-way analysis of variance. Significance of difference was calculated with the Tukey Honestly Significant Difference test for factor analysis. Categorical variables were compared with Fisher’s exact test. We performed logistic multivariate regression analysis to determine clinical and transthoracic echocardiographic factors for predicting LAA thrombus formation; clinical factors used for analysis were age, gender, history of hypertension, diabetes mellitus, previous stroke, congestive heart failure, structural heart disease, type of AF (paroxysmal or persistent), and state of anticoagulant therapy. Echocardiographic parameters were LA diameter, LV end-diastolic dimension, ejection fraction, LV mass index, relative wall thickness, presence of at least moderate mitral regurgitation, and E/e= ⱖ13. We performed receiver operator curve analysis to determine the optimal cut-off value of E/e= for predicting LAA thrombus. Differences were considered statistically significant at a p value ⬍0.05 (2-sided). JMP 5.0.1 (SAS Institute, Cary, North Carolina) was used for statistical analysis.
Arrhythmias and Conduction Disturbances/Diastolic Filling Pressure and LA Thrombus
Figure 1. Patients were categorized into 4 groups based on quartile (Q) of the ratio of early transmitral flow velocity to mitral annular velocity (ratio ranges). Incidence of left atrial appendage thrombus (vertical bar) in the fourth quartile of the ratio of early transmitral flow velocity to mitral annular velocity (E/e=) was significantly (p ⬍0.0001) higher than those in the other 3 groups.
Results LAA thrombi were observed in 28 patients (7.4%) on transesophageal echocardiogram. Patients with LAA thrombi were significantly older and had higher prevalence of persistent AF and of structural heart disease than those without thrombus (Table 1). More patients with thrombi were in AF at transesophageal echocardiography than were those without thrombus. Numbers of patients receiving warfarin were comparable between those with and without thrombi. International normalized ratio of prothrombin time showed no differences between the 2 subsets of those receiving warfarin. Incidences of hypertension and diabetes showed no differences between the 2 subsets. Previous stroke and heart failure were more frequently observed in patients with LAA thrombi. Therefore, patients with thrombi had significantly higher CHADS2 scores than those without thrombus. Transthoracic echocardiography was performed before or after transesophageal echocardiography with median of 6-day interval (25% to 75% quartile, 3 to 9 days). E/e= was significantly higher in patients with LAA thrombi than in those without thrombus (18.3 ⫾ 9.3 vs 11.4 ⫾ 5.9, p ⬍0.0001). Patients with LAA thrombi also had larger LA diameters and LV end-diastolic dimension, lower ejection fraction, and higher prevalence of at least moderate mitral regurgitation than those without thrombus (Table 2). There were no significant differences in relative wall thickness and LV mass index. We divided the study patients into 4 groups based on quartile of E/e=. E/e= ⬎15, a widely used estimate of increased LV filling pressure,2,3 was observed in 75 of 94 patients in the fourth quartile (E/e= ⬎13.6). Nineteen of 28 patients with LAA thrombi were in quartile 4, and quartile 4 had more patients with LAA thrombi than the other 3 groups (p ⬍0.0001; Figure 1). However, only 19 of 94 patients (20.2%) in quartile 4 had LAA thrombi. Receiver operator curve analysis demonstrated that 12.8 was the optimal cut-off value of E/e= for predicting LAA
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Figure 2. Receiver operator curve analysis indicated that 12.8 was the optimal cut-off value of the ratio of transmitral early mitral valve flow velocity to mitral annular velocity for predicting left atrial appendage thrombi (area under the curve 0.77). Table 3 Predictors of left atrial appendage thrombus among clinical and transthoracic echocardiographic parameters
Ejection fraction Early transmitral flow velocity/mitral annular velocity ⱖ13 Left atrial diameter Persistent atrial fibrillation Left ventricular end-diastolic dimension Heart failure Mitral regurgitation at least moderate grade Age Gender Left ventricular mass index Relative wall thickness Anticoagulation therapy Atrial fibrillation during transesophageal echocardiography Diabetes mellitus Structural heart disease Previous stroke Hypertension
Wald Chisquare
p Value
7.97 5.26
0.005 0.02
4.32 3.06 2.07 2.17 2.09 1.01 0.75 0.62 0.42 0.51 0.72
0.04 0.08 0.15 0.14 0.15 0.32 0.39 0.43 0.52 0.48 0.70
0.18 0.06 0.06 0.007
0.67 0.80 0.80 0.93
thrombus (area under the curve 0.77; Figure 2). Based on an equation by Nagueh et al,1 E/e= equal to 12.8 corresponds to 20 mm Hg of LV filling pressure. E/e= ⬎12.8 predicted presence of LAA thrombus with 75.0% sensitivity and 74.4% specificity. Using clinical and transthoracic echocardiographic parameters, we performed logistic multivariate analysis to determine the predictors for LAA thrombi. We used E/e= ⱖ13 as a factor for analysis. LA diameter, LV ejection fraction, and E/e= ⱖ13 were selected as significant predictors for LAA thrombus among clinical and echocardiographic parameters (Table 3). E/e= ⱖ13 had an odds ratio of 3.50 (95% confidence interval 1.22 to 10.61) for LAA thrombus. We investigated relations between E/e= and LAA emptying flow velocity. Patients with LAA thrombi had lower
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Figure 3. (Left) Ratio of early transmitral flow velocity to mitral annular velocity (E/e=) was weakly but significantly correlated with left atrial appendage flow velocity (r ⫽ 0.2, p ⫽ 0.0002); 95% confidence intervals (dashed lines) are shown for the regression line. (Right) When study patients were categorized into 4 groups based on quartile of the ratio of early transmitral flow velocity to mitral annular velocity, an increased ratio quartile was associated with lower left atrial appendage blood flow velocity (p ⫽ 0.0005 by analysis of variance). Quartile 4 had significantly lower velocity than quartiles 1 and 2, whereas no significant differences were observed among quartiles 1, 2, and 3. *p ⫽ 0.03; **p ⫽ 0.0002 versus quartile 4. Abbreviation as in Figure 1.
(24 patients, 20%, vs 4 patients, 1.6%, p ⬍0.0001). They also had significant larger LA dimension (4.2 ⫾ 0.6 vs 3.6 ⫾ 0.5 cm, p ⬍0.0001). Patients with SEC had higher E/e= than those without SEC (15.2 ⫾ 7.9 vs 10.4 ⫾ 4.9, p ⬍0.0001). Increased E/e= quartile was associated with higher prevalence of SEC (p ⬍0.0001; Figure 4). Discussion
Figure 4. Prevalence of spontaneous echo contrast in study patients based on ratio of early transmitral flow velocity to mitral annular velocity (ratio ranges). Increased quartile of the ratio of early transmitral flow velocity to mitral annular velocity was associated with higher rates of spontaneous echo contrast (p ⬍0.0001). Abbreviation as in Figure 1.
LAA flow velocity than those without thrombus (30.7 ⫾ 12.4 vs 44.8 ⫾ 20.1 cm/s, p ⫽ 0.002). E/e= ratio was weakly but significantly correlated with LAA flow velocity (r ⫽ 0.2, p ⫽ 0.0002). Increased E/e= quartile was significantly associated with decreased LAA flow velocity (p ⫽ 0.0005 by analysis of variance). Quartile 4 had significantly lower velocity than quartiles 1 and 2 (quartile 4 vs 1 37.2 ⫾ 17.5 vs 49.7 ⫾ 22.8 cm/s, p ⫽ 0.0002, vs quartile 2 45.3 ⫾ 19.2 cm/s, p ⫽ 0.03, vs quartile 3 44.7 ⫾ 18.7 cm/s, p ⫽ 0.13), although there were no significant differences among quartiles 1, 2, and 3 (Figure 3). LAA flow velocity was also weakly correlated with LA dimension (r ⫽ 0.36, p ⬍0.0001). SEC was observed in 24 patients (85.7%) with LAA thrombi and in only 96 patients (27.6%, p ⬍0.0001) without thrombi (Table 2). Patients with SEC had significantly higher incidences of LAA thrombi than those without SEC
LAA thrombi were observed on transesophageal echocardiogram in 28 of 376 patients (7.4%) with AF, and patients with LAA thrombi had higher E/e= than those without thrombus. Most patients with thrombi were in quartile 4 of E/e=, and E/e= equal to 12.8 (corresponding to about 20 mm Hg of filling pressure) was the optimal cut-off point for predicting LAA thrombus. Multivariate logistic analysis selected LA diameter, LV ejection fraction, and E/e= ⱖ13 as significant predictors for LAA thrombus among clinical and echocardiographic parameters. Odds ratio of E/e= ⱖ13 for LAA thrombi was 3.50 (95% confidence interval 1.22 to 10.61). E/e= was associated with LAA flow velocity and with incidence of SEC, suggesting that LV diastolic dysfunction could contribute to LAA thrombosis, at least partly, through impairment of LAA emptying function and blood stasis within the left atrium. LAA thrombi were more frequently observed in quartile 4 of E/e= and no differences were observed among the other 3 quartiles. Thus, LAA thrombus formation is related to increased LV filling pressure, although its increase within normal range might not exacerbate thrombus formation. LA function is preserved at the early phase of LV diastolic dysfunction, but further increase in LV filling pressure increases workload on the LA myocardium and causes LA dysfunction.16 LAA blood flow velocity was decreased in quartile 4 of E/e= compared to that in other quartiles, although the correlation between E/e= and LAA flow velocity was very weak, indicating that LAA function was attenuated by increased LA filling pressure. Previous studies also demonstrated that increased LV diastolic filling pressure atten-
Arrhythmias and Conduction Disturbances/Diastolic Filling Pressure and LA Thrombus
uates LAA blood flow velocity in AF17 and in sinus rhythm.18,19 In contrast, incidence of SEC was increased as was quartile of E/e=, indicating that blood stasis within the left atrium could be exacerbated by an increase in diastolic filling pressure even within normal range. Prevalence of LA thrombus in AF is associated with density grade of SEC.20 Higher diastolic filling pressure might be related to a higher grade of SEC, although the grade of SEC was not evaluated in the present study. Multivariate analysis demonstrated that LA dimension and E/e= ⱖ13 were independent factors for LAA thrombus. However, increased filling pressure could exert its effects through secondary changes in LA size. An enlarged left atrium is also associated with higher incidences of SEC21 and with LAA dysfunction,22 which was also demonstrated in the present study. LA dilatation in patients with nonvalvular chronic AF is associated with an increase in coagulate factors23 and with endothelial dysfunction.24 Measurement of E/e= might have only limited ability to predict LA thrombus in AF. In contrast, the present results suggest the possibility that treatment of diastolic dysfunction could decrease the risk of stroke in the high-risk AF population. Increased diastolic filling pressure is reported to be associated with all-cause mortality in patients with nonvalvular AF.25 A prospective study to investigate the effects of treatment of diastolic dysfunction on thrombosis in AF is expected. Because the present study was retrospective, the results should be interpreted carefully. E/e= measured during AF could be less accurate than in the sinus rhythm, although it might be somehow correlated with diastolic filling pressure. Prevalence of heart failure might be higher than in the general AF population,26 although a similar prevalence was reported in another large-scale trial of AF.27 One explanation was that the present study was conducted in a tertiary hospital. We might have overestimated incidence of heart failure because of a difficulty in differentiating symptoms due to heart failure from those due to AF. The number of patients receiving warfarin might be smaller than expected. A substantial proportion of patients underwent transesophageal echocardiography just before catheter ablation, and warfarin was temporarily stopped. Modest CHADS2 scores in the present patients (1.5 ⫾ 1.3) could be another reason for the lower rate of warfarin treatment. International normalized ratio of prothrombin time in patients receiving warfarin (1.9 ⫾ 0.7) might be lower than the optimal therapeutic range, and this was because a range from 1.6 to 2.1 is recommended for elderly patients with AF in Japan.28 We did not determine frequency and/or duration of AF episodes in patients with paroxysmal AF, although increased LV filling pressure might increase the number of paroxysmal AF episodes.29 In conclusion, increased diastolic filling pressure, estimated as E/e=, could be associated with higher frequency of LAA thrombus in patients with AF. Blood stasis or impaired LAA function could partly contribute to an increase in LAA thrombosis.
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