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Relation of the severity of mitral regurgitation to thromboembolic risk in patients with atrial fibrillation
International Journal of Cardiology 146 (2011) 197–201
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Relation of the severity of mitral regurgitation to thromboembolic risk in patients with atrial fibrillation Nobuyuki Fukuda, Tadakazu Hirai, Kazumasa Ohara, Keiko Nakagawa, Takashi Nozawa, Hiroshi Inoue ⁎ The Second Department of Internal Medicine, University of Toyama, Japan
a r t i c l e
i n f o
Article history: Received 9 April 2009 Received in revised form 12 June 2009 Accepted 26 June 2009 Available online 6 August 2009 Keywords: Atrial fibrillation Mitral regurgitation D-dimer Transesophageal echocardiography
a b s t r a c t Background: Patients with atrial fibrillation (AF) are at risk for thromboembolism. Although mitral regurgitation (MR) could be protective against left atrial (LA) blood stasis, the relationship between the severity of MR and thromboembolic risk has not been clarified in patients with AF. Methods: 271 patients with permanent AF underwent transesophageal echocardiography (TEE). The severity of MR was assessed by Doppler echocardiography. LA blood stasis on TEE and plasma D-dimer levels were used to evaluate the thromboembolic risk. Results: Patients with severe MR (n = 20) had significantly higher LA appendage peak flow velocity compared to those with no MR (n = 114) and those with only mild MR (n = 92) (p b 0.05). The grade of LA spontaneous echo contrast (SEC) was lower in patients with severe MR compared to those with no, mild or moderate MR (severe MR 0.7 ± 0.7 grade vs moderate MR 1.7 ± 1.0 grade, mild MR 2.2 ± 1.3 grade, and no MR 1.9 ± 1.3 grade, p b 0.05). Multivariate analysis revealed severe MR as a negative predictor of LA blood stasis on TEE findings (odds ratio 0.27; 95% confidence interval 0.09-0.86, p b 0.05). By contrast, D-dimer level was significantly higher in patients with moderate MR compared to those with any other type of severity of MR (moderate MR 1.72 ± 1.45 µg/ml vs severe MR 0.76 ± 0.95 µg/ml, mild MR 0.97 ± 1.09 µg/ml, and no MR 0.82 ± 1.15 µg/ml, p b 0.05). Conclusions: There is a protective effect of MR on LA blood stasis, but this beneficial effect on thromboembolic risk appears to be limited to patients with severe MR. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patients with atrial fibrillation (AF) are at increased risk for thromboembolism, especially if they are advanced in age, have a history of hypertension, diabetes mellitus or heart failure or have had a previous stroke or transient ischemic attack [1,2]. These factors have been identified as independent risk factors for thromboembolic risk [3]. Several risk-stratification schemes have been used to identify AF patients who might benefit from oral anticoagulation [4]. Recent guidelines for the management of patients with AF recommend that anticoagulation treatment should be tailored individually according to comorbidities [2]. Although several studies have demonstrated lower prevalence of embolic events in patients with mitral regurgitation (MR), [5–10] others have not [11–13]. It remains unclear, therefore, whether MR can reduce embolic events in AF. During AF, stagnant blood flow in the left atrial appendage (LAA) can contribute to a hypercoagulable state and subsequent clot formation in the fibrillating atria. Elevated levels of hemostatic markers are
⁎ Corresponding author. The Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Fax: +81 76 434 5026. E-mail address: [email protected] (H. Inoue). 0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.051
also present in patients with nonvalvular AF [14]. D-dimer levels can predict subsequent embolic events in patients with the nonvalvular AF [15]. However, few studies have evaluated D-dimer levels in patients with AF who also have MR. In the present study, therefore, we aimed to clarify the relationship between severity of MR and thromboembolic risk in patients with nonrheumatic AF. 2. Methods 2.1. Study patients We retrospectively studied 271 consecutive patients with permanent AF (181 men, and 90 women; mean age, 67 ± 12 years) who had underwent transesophageal echocardiography (TEE) and hemostatic marker evaluation. The patients were referred for either identification of a potential cardiogenic source of emboli or evaluation of stroke risk. The study protocol was approved by our institutional ethics committee and informed consent was obtained from all patients. Permanent AF was confirmed electrocardiogaphically on at least 2 separate occasions (4 weeks apart). Additional clinical characteristics were assessed, including any history of diabetes mellitus, hyperlipidemia, hypertension, previous cerebral or peripheral embolic event, or congestive heart failure. In addition, the physical status of each patient was determined using the New York Heart Association (NYHA) functional class, and the use of oral anticoagulant agents at the time of echocardiographic studies was determined from history, medical records and routine laboratory data. Patients with rheumatic mitral valvular diseases, prosthetic valve replacement or infective endocarditis were excluded.
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2.2. Echocardiography All patients underwent transthoracic echocardiography (TTE) and TEE studies. Briefly, TTE was performed using a 3-MHz transducer connected to an ultrasound machine (SSA770A, Toshiba, Tokyo, Japan). The severity of MR was assessed based on the ratio of color flow regurgitant area to left atrial (LA) area and graded as none, mild, moderate or severe using the American Society of Echocardiography (ASE) guidelines (Fig. 1) [16,17]. MR was considered severe if the MR jet area was ≥40% of LA area; mild if the MR jet area was b 20% of LA area; and moderate if the area was larger than the mild type but less than the severe type of MR, which was estimated by average appearance of MR jet area for 5 cardiac cycles [18]. MR etiology was characterized as due to prolapse, poor coaptation, tethering due to left ventricular dysfunction, papillary muscle dysfunction or tendon rupture of mitral valve leaflets, based on the conventional echocardiographic criteria [16]. LA dimension, left ventricular diastolic diameter (LVDd) and left ventricular ejection fraction (LVEF) were also determined using M-mode scanning. TEE was performed with a 5-MHz multiplanar transducer. Each patient was studied in the fasting state without premedication except for topical anesthesia of the hypopharynx with lidocaine spray. Multiple standard tomographic planes were imaged. The severity of LA spontaneous echo contrast (LASEC) and LAA peak flow velocity were both determined. LASEC was diagnosed by the presence of dynamic smoke-like echoes within the LA or LAA with a characteristic swirling motion that was distinct from white noise artifact. The severity of LASEC was defined by the criteria of Fatkin et al [19]; 0 = none (absence of echogenicity); 1+ = mild (minimal echogenicity detectable only transiently during the cardiac cycle with optimal gain settings); 2+ = mild to moderate (transient spontaneous echocardiographic contrast without increased gain settings and more dense pattern than 1+); 3+ = moderate (dense swirling pattern during the entire cardiac cycle); and 4+ = severe (intense echodensity and very slow swirling patterns in the LAA, usually with a similar density in the main left atrial cavity). LAA flow velocity profiles were obtained by pulse-wave Doppler echocardiographic interrogation at the orifice of the appendage. Peak outflow velocity signals within each R-R interval were averaged over a minimum of 6 cardiac cycles. 2.3. Determination of hemostatic markers The plasma level of D-dimer was used as a marker for active fibrinolysis. Blood samples were obtained for determination of D-dimer levels on the day of the TEE study using the 2-syringe technique, as outlined in a previous study [15]. D-dimer levels were measured using an enzyme-linked immunosorbent assay kits (Behring Werke AG, Marburg, Germany). In patients treated with warfarin, PT-INR was also determined.
3. Statistical analyses Data are presented as mean value ± SD. Intergroup differences for continuous variables were evaluated by analysis of variance (ANOVA) followed by the post hoc Bonferroni test. Chi-square test or Fisher's exact probability test, if indicated, was used to compare the categorical variables (SPSS 14.0; SPSS, Chicago, IL, USA). A p-value b 0.05 was considered significant. High grade (dense) SEC (≥grade 3+) or reduced LAA flow velocity (≤20 cm/s) was considered a thromboembolic risk factor by echocardiography. To compare the echocardiographic and clinical findings, patients with AF were categorized into 4 groups according to the severity of MR on TTE (Fig. 1). Multivariate logistic regression analysis was used to determine independent positive and negative predictors of thromboembolic risk. Variables tested were advanced age (≥75 years old), presence of heart failure, hypertension, diabetes mellitus, and cerebral infarction, gender, LA dimension, LVDd, LVEF and the severity of the MR. 4. Results Of the 271 patients with permanent AF, 20 patients had severe MR, 45 had moderate MR and 92 had only mild MR on TTE. Table 1 shows the clinical characteristics including prevalence of anticoagulation therapy and PT-INR on the day of the TEE study. Prevalence of heart failure and NYHA class was higher in patients with moderate and severe MR compared to those without MR. PT-INR in patients treated with warfarin was similar among the 4 groups. Table 2 shows the echocardiographic findings. LA size and LVDd measured with M-mode were significantly larger in patients with severe MR compared to the remaining 3 groups of patients, while LVEF was comparable regardless of the severity of MR. Poor coaptation and mitral valve prolapse were the most common causes of MR in our study patients (Table 2).
Fig. 1. Semiquantitative visual assessment of the severity of mitral regurgitation. Four grades of severity are shown, based on the ratio of color flow regurgitant area to left atrial area on transthoracic echocardiography.
N. Fukuda et al. / International Journal of Cardiology 146 (2011) 197–201
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Table 1 Clinical characteristics of patients. Severity of mitral regurgitation
Men Age (years) NYHA 2 or more Heart failure Hypertension Diabetes mellitus Prior stroke or TIA Hyperlipidemia Warfarin PT-INR
No
Mild
Moderate
Severe
(n = 114)
(n = 92)
(n = 45)
(n = 20)
80(70) 65.2 ± 10.8 24(21) 24(21) 46(40) 10(9) 29(25) 18(16) 60(52) 1.86 ± 1.51
62(66) 67.5 ± 11.5 25(27) 33(36) 35(38) 20(22)† 26(28) 15(16) 55(60) 1.77 ± 1.08
29(64) 70.6 ± 11.5 23(51) †‡ 23(51) † 20(44) 8(18) 10(22) 8(18) 27(60) 1.78 ± 0.87
10(50) 67.2 ± 14.9 15(75) †‡ 16(80) †‡ 4(20) 1(5) 5(25) 0(0) 10(50) 2.13 ± 2.25
Values are number of patients (%) or mean ± SD. NYHA = New York Heart Association functional class, TIA= transient ischemic attack, PT-INR = prothrombin time ineternational normalized ratio. †p b 0.05 versus no MR group, ‡p b 0.05 versus mild MR group.
The TEE findings showed that patients with severe MR had higher LAA peak flow velocity (35.2 ± 17.6 cm/s) compared to those with no MR (25.7 ± 14.7 cm/s) and mild MR (25.4 ± 13.8 cm/s) (p b 0.05, Fig. 2). In addition, the severity of LASEC was significantly lower in patients with severe MR (0.7 ± 0.7) compared to those with no MR (1.9 ± 1.3), mild MR (2.2 ± 1.3) and moderate MR (1.7 ± 1.0) (p b 0.05, Fig. 3). Seven percent of patients with no MR had LAA thrombi, while 10.9% of those with mild MR and 8.9% of those with moderate MR had thrombi in their LAA. None of the patients with severe MR had LAA thrombi. However, the difference in the frequency of LAA thrombi did not reach the statistical significance (p value = 0.41). Multiple logistic analysis demonstrated that severe MR was a negative predictor (odds ratio 0.27; 95% confidence interval (CI), 0.09–0.86; p b 0.05) and advanced age was a positive predictor (odds ratio 2.43; 95% CI, 1.30– 4.55; p b 0.01) of dense LASEC (≥grade 3) or reduced LAA flow velocity (≤20 cm/s). D-dimer levels increased as the severity of MR increased, but not for patients with severe MR (Fig. 4). Patients with moderate MR showed significantly higher D-dimer levels (1.72 ± 1.45 µg/ml) compared to those without MR (0.82 ± 1.15 µg/ml), mild MR (0.97 ± 1.09 µg/ml) and severe MR (0.76 ± 0.95 µg/ml) (p b 0.05). There was no difference in D-dimer levels among the different etiologies of MR. 4. Discussion Based on TEE findings and D-dimer levels, patients with nonrheumatic AF who have severe MR would appear to have lower thromboembolic risk than those with mild or moderate MR. This might be due to MR blood stream preventing formation of thrombi in LAA of patients with severe MR. In addition, AF patients with Table 2 Echocardiographic variables. Severity of mitral regurgitation
LAD (mm) LVDd (mm) LVEF (%) Etiology of MR Prolapse Ruptured chordae Tethering Poor coaptation
No
Mild
Moderate
Severe
(n = 114)
(n = 92)
(n = 45)
(n = 20)
40 ± 8 47 ± 9 60 ± 11
45 ± 8† 50 ± 7† 55 ± 13†
49 ± 9† 53 ± 9† 54 ± 16
55 ± 10†‡§ 57 ± 10†‡ 59 ± 10
7(8) 0(0) 4(4) 81(88)
7(16) 0(0) 3(7) 35(78)
9(45) 3(15) 1(5) 7(35)
Values are number of patients (%) or mean ± SD. LAD = left atrial dimension, LVDd = left ventricular diastolic diameter, LVEF = left ventricular ejection fraction. †p b 0.05 versus no MR group, ‡p b 0.05 versus mild MR group, §p b 0.05 versus moderate MR group.
Fig. 2. Relationship between the severity of mitral regurgitation (MR) and left appendage flow velocity. Note the high flow velocity in the severe MR group. Mean ± SD.
moderate MR had increased D-dimer levels when compared to those without MR. AF with heart failure could result in hypercoagulability in the LA via endothelial damage and dysfunction [20]. Thus, the Ddimer levels in patients with MR could be affected not only by the blood flow in LAA but also by clinical risk factors including heart failure and aging. Previous studies showed that TEE findings correlated with stroke risk in patients with nonvalvular AF [21,22]. Reduced LAA flow velocities (LAA peak velocity ≤ 20 cm/s) and dense LASEC have presaged thrombus formation. Significant MR has been reported to prevent blood stasis in the LA cavity and reduce the thromboembolic risk in patients with AF [7,9]. In the present study, patients with severe MR had faint SEC and higher LAA peak flow velocity compared to those with mild MR. The presence of severe MR increased regurgitant volume, thereby reducing SEC but increasing LAA flow velocity, when compared with mild to moderate MR. Our findings are in agreement with previous echocardiographic data of Movsowitz et al. who showed that increased severity of MR decreased the prevalence SEC and thrombi on TEE [9]. However, their study included subject who had sinus rhythm, and only 89 patients with atrial fibrillation were studied [9]. In contrast, we studied a larger number of patients. We studied only patients with permanent AF, because the frequency and duration of AF in patients with paroxysmal AF can affect LAA function. Similar to other studies which showed that plasma levels of Ddimer were increased in patients with nonvalvular AF, [23] we demonstrated in a previous study that increased levels of D-dimer correlated with increased thromboembolic risk [15]. Patients with elevated levels of D-dimer had higher incidence of thromboembolic events [15]. In our study, the levels of D-dimer were higher in patients with moderate MR compared to those with severe MR, suggesting that prevention of LA blood stagnation improved hypercoagulable state, at least in part, in patients with nonrheumatic AF. Fukazawa et al. also found that plasma levels of prothrombin fragment 1 + 2, thrombinantithrombin III complex, and D-dimer were significantly lower in nonrheumatic AF patients who had moderate to severe MR compared to patients without significant MR [5]. However, the number of patients in their study was small and the severity of MR was classified into only 2 groups; i.e., the ‘no MR or mild MR’ group versus ‘moderate to severe MR’ group. Since TEE findings were not available in their study, the precise mechanism for the reduction in the levels of hemostatic markers remains unclear. Miyasaka et al. also reported an increased prevalence of thromboembolic events in patients with mild MR when compared with those with higher grades of MR [11]. In our study, we also found that patients with mild to moderate MR had significantly increased LASEC and D-dimer levels, indicating that these patients were at increased risk of thromboembolism.
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Fig. 3. Relation between the severity of MR and left atrial spontaneous echo contrast (SEC). Note the reduced left atrial SEC in the severe MR group. Mean ± SD.
The presence of severe MR reduced markers of embolic risks, as determined by TEE findings and D-dimer levels, when compared to those with moderate MR. Patients with moderate MR exhibited the highest D-dimer levels among the 4 groups in our current study. The increased thromboembolic risk may be attributable to heart failure in the moderate MR group, since heart failure was identified as a thromboembolic risk factor in previous studies [3]. Therefore, moderate MR does not reduce embolic risk and patients with moderate MR may require intensive anticoagulant therapy. In patients with severe MR, the MR jet may agitate blood stasis in LA cavity, reducing LASEC and increasing LAA blood flow. 4.1. Study limitations Our study is limited by the fact that it retrospectively evaluated thromboembolic risk in patients with MR. Further prospective studies are still needed to reach any definitive conclusion regarding thromboembolic risk in patients with MR. Our choice to include patients on anticoagulant therapy may also have biased our results. Although there were no significant differences in the frequency of warfarin treatment and intensity of anticoagulation (PT-INR) among the 4 patient groups, levels of D-dimer in no MR and mild MR groups were not increased as compared with our previous nonvalvular AF patients who did not receive anticoagulation therapy [15]. In addition, warfarin therapy itself has not been shown to affect the presence and severity of LASEC [24]. Finally, our study may have had a selection bias. Because the study patients underwent TEE for evaluation of potential cardiac source of emboli, our findings would, by necessity, include results from patients at high risk for thromboembolism. The identification of MR grades using color-coded MR signals is also prone to substantial interobserver variability in patients with nonrheumatic AF, possibly due to the irregularity of cardiac cycles. 5. Conclusion The present study suggests that AF patients with severe MR are at lower thromboembolic risk compared to AF patients with mild to moderate MR. In addition, AF patients with moderate MR may have a higher thromboembolic risk. Acknowledgment The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [25].
Fig. 4. Effect of the severity of MR on plasma D-dimer levels. Mean ± SD.
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Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Relation of the severity of mitral regurgitation to thromboembolic risk in patients with atrial fibrillation Nobuyuki Fukuda, Tadakazu Hirai, Kazumasa Ohara, Keiko Nakagawa, Takashi Nozawa, Hiroshi Inoue ⁎ The Second Department of Internal Medicine, University of Toyama, Japan
a r t i c l e
i n f o
Article history: Received 9 April 2009 Received in revised form 12 June 2009 Accepted 26 June 2009 Available online 6 August 2009 Keywords: Atrial fibrillation Mitral regurgitation D-dimer Transesophageal echocardiography
a b s t r a c t Background: Patients with atrial fibrillation (AF) are at risk for thromboembolism. Although mitral regurgitation (MR) could be protective against left atrial (LA) blood stasis, the relationship between the severity of MR and thromboembolic risk has not been clarified in patients with AF. Methods: 271 patients with permanent AF underwent transesophageal echocardiography (TEE). The severity of MR was assessed by Doppler echocardiography. LA blood stasis on TEE and plasma D-dimer levels were used to evaluate the thromboembolic risk. Results: Patients with severe MR (n = 20) had significantly higher LA appendage peak flow velocity compared to those with no MR (n = 114) and those with only mild MR (n = 92) (p b 0.05). The grade of LA spontaneous echo contrast (SEC) was lower in patients with severe MR compared to those with no, mild or moderate MR (severe MR 0.7 ± 0.7 grade vs moderate MR 1.7 ± 1.0 grade, mild MR 2.2 ± 1.3 grade, and no MR 1.9 ± 1.3 grade, p b 0.05). Multivariate analysis revealed severe MR as a negative predictor of LA blood stasis on TEE findings (odds ratio 0.27; 95% confidence interval 0.09-0.86, p b 0.05). By contrast, D-dimer level was significantly higher in patients with moderate MR compared to those with any other type of severity of MR (moderate MR 1.72 ± 1.45 µg/ml vs severe MR 0.76 ± 0.95 µg/ml, mild MR 0.97 ± 1.09 µg/ml, and no MR 0.82 ± 1.15 µg/ml, p b 0.05). Conclusions: There is a protective effect of MR on LA blood stasis, but this beneficial effect on thromboembolic risk appears to be limited to patients with severe MR. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patients with atrial fibrillation (AF) are at increased risk for thromboembolism, especially if they are advanced in age, have a history of hypertension, diabetes mellitus or heart failure or have had a previous stroke or transient ischemic attack [1,2]. These factors have been identified as independent risk factors for thromboembolic risk [3]. Several risk-stratification schemes have been used to identify AF patients who might benefit from oral anticoagulation [4]. Recent guidelines for the management of patients with AF recommend that anticoagulation treatment should be tailored individually according to comorbidities [2]. Although several studies have demonstrated lower prevalence of embolic events in patients with mitral regurgitation (MR), [5–10] others have not [11–13]. It remains unclear, therefore, whether MR can reduce embolic events in AF. During AF, stagnant blood flow in the left atrial appendage (LAA) can contribute to a hypercoagulable state and subsequent clot formation in the fibrillating atria. Elevated levels of hemostatic markers are
⁎ Corresponding author. The Second Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Fax: +81 76 434 5026. E-mail address: [email protected] (H. Inoue). 0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.051
also present in patients with nonvalvular AF [14]. D-dimer levels can predict subsequent embolic events in patients with the nonvalvular AF [15]. However, few studies have evaluated D-dimer levels in patients with AF who also have MR. In the present study, therefore, we aimed to clarify the relationship between severity of MR and thromboembolic risk in patients with nonrheumatic AF. 2. Methods 2.1. Study patients We retrospectively studied 271 consecutive patients with permanent AF (181 men, and 90 women; mean age, 67 ± 12 years) who had underwent transesophageal echocardiography (TEE) and hemostatic marker evaluation. The patients were referred for either identification of a potential cardiogenic source of emboli or evaluation of stroke risk. The study protocol was approved by our institutional ethics committee and informed consent was obtained from all patients. Permanent AF was confirmed electrocardiogaphically on at least 2 separate occasions (4 weeks apart). Additional clinical characteristics were assessed, including any history of diabetes mellitus, hyperlipidemia, hypertension, previous cerebral or peripheral embolic event, or congestive heart failure. In addition, the physical status of each patient was determined using the New York Heart Association (NYHA) functional class, and the use of oral anticoagulant agents at the time of echocardiographic studies was determined from history, medical records and routine laboratory data. Patients with rheumatic mitral valvular diseases, prosthetic valve replacement or infective endocarditis were excluded.
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2.2. Echocardiography All patients underwent transthoracic echocardiography (TTE) and TEE studies. Briefly, TTE was performed using a 3-MHz transducer connected to an ultrasound machine (SSA770A, Toshiba, Tokyo, Japan). The severity of MR was assessed based on the ratio of color flow regurgitant area to left atrial (LA) area and graded as none, mild, moderate or severe using the American Society of Echocardiography (ASE) guidelines (Fig. 1) [16,17]. MR was considered severe if the MR jet area was ≥40% of LA area; mild if the MR jet area was b 20% of LA area; and moderate if the area was larger than the mild type but less than the severe type of MR, which was estimated by average appearance of MR jet area for 5 cardiac cycles [18]. MR etiology was characterized as due to prolapse, poor coaptation, tethering due to left ventricular dysfunction, papillary muscle dysfunction or tendon rupture of mitral valve leaflets, based on the conventional echocardiographic criteria [16]. LA dimension, left ventricular diastolic diameter (LVDd) and left ventricular ejection fraction (LVEF) were also determined using M-mode scanning. TEE was performed with a 5-MHz multiplanar transducer. Each patient was studied in the fasting state without premedication except for topical anesthesia of the hypopharynx with lidocaine spray. Multiple standard tomographic planes were imaged. The severity of LA spontaneous echo contrast (LASEC) and LAA peak flow velocity were both determined. LASEC was diagnosed by the presence of dynamic smoke-like echoes within the LA or LAA with a characteristic swirling motion that was distinct from white noise artifact. The severity of LASEC was defined by the criteria of Fatkin et al [19]; 0 = none (absence of echogenicity); 1+ = mild (minimal echogenicity detectable only transiently during the cardiac cycle with optimal gain settings); 2+ = mild to moderate (transient spontaneous echocardiographic contrast without increased gain settings and more dense pattern than 1+); 3+ = moderate (dense swirling pattern during the entire cardiac cycle); and 4+ = severe (intense echodensity and very slow swirling patterns in the LAA, usually with a similar density in the main left atrial cavity). LAA flow velocity profiles were obtained by pulse-wave Doppler echocardiographic interrogation at the orifice of the appendage. Peak outflow velocity signals within each R-R interval were averaged over a minimum of 6 cardiac cycles. 2.3. Determination of hemostatic markers The plasma level of D-dimer was used as a marker for active fibrinolysis. Blood samples were obtained for determination of D-dimer levels on the day of the TEE study using the 2-syringe technique, as outlined in a previous study [15]. D-dimer levels were measured using an enzyme-linked immunosorbent assay kits (Behring Werke AG, Marburg, Germany). In patients treated with warfarin, PT-INR was also determined.
3. Statistical analyses Data are presented as mean value ± SD. Intergroup differences for continuous variables were evaluated by analysis of variance (ANOVA) followed by the post hoc Bonferroni test. Chi-square test or Fisher's exact probability test, if indicated, was used to compare the categorical variables (SPSS 14.0; SPSS, Chicago, IL, USA). A p-value b 0.05 was considered significant. High grade (dense) SEC (≥grade 3+) or reduced LAA flow velocity (≤20 cm/s) was considered a thromboembolic risk factor by echocardiography. To compare the echocardiographic and clinical findings, patients with AF were categorized into 4 groups according to the severity of MR on TTE (Fig. 1). Multivariate logistic regression analysis was used to determine independent positive and negative predictors of thromboembolic risk. Variables tested were advanced age (≥75 years old), presence of heart failure, hypertension, diabetes mellitus, and cerebral infarction, gender, LA dimension, LVDd, LVEF and the severity of the MR. 4. Results Of the 271 patients with permanent AF, 20 patients had severe MR, 45 had moderate MR and 92 had only mild MR on TTE. Table 1 shows the clinical characteristics including prevalence of anticoagulation therapy and PT-INR on the day of the TEE study. Prevalence of heart failure and NYHA class was higher in patients with moderate and severe MR compared to those without MR. PT-INR in patients treated with warfarin was similar among the 4 groups. Table 2 shows the echocardiographic findings. LA size and LVDd measured with M-mode were significantly larger in patients with severe MR compared to the remaining 3 groups of patients, while LVEF was comparable regardless of the severity of MR. Poor coaptation and mitral valve prolapse were the most common causes of MR in our study patients (Table 2).
Fig. 1. Semiquantitative visual assessment of the severity of mitral regurgitation. Four grades of severity are shown, based on the ratio of color flow regurgitant area to left atrial area on transthoracic echocardiography.
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Table 1 Clinical characteristics of patients. Severity of mitral regurgitation
Men Age (years) NYHA 2 or more Heart failure Hypertension Diabetes mellitus Prior stroke or TIA Hyperlipidemia Warfarin PT-INR
No
Mild
Moderate
Severe
(n = 114)
(n = 92)
(n = 45)
(n = 20)
80(70) 65.2 ± 10.8 24(21) 24(21) 46(40) 10(9) 29(25) 18(16) 60(52) 1.86 ± 1.51
62(66) 67.5 ± 11.5 25(27) 33(36) 35(38) 20(22)† 26(28) 15(16) 55(60) 1.77 ± 1.08
29(64) 70.6 ± 11.5 23(51) †‡ 23(51) † 20(44) 8(18) 10(22) 8(18) 27(60) 1.78 ± 0.87
10(50) 67.2 ± 14.9 15(75) †‡ 16(80) †‡ 4(20) 1(5) 5(25) 0(0) 10(50) 2.13 ± 2.25
Values are number of patients (%) or mean ± SD. NYHA = New York Heart Association functional class, TIA= transient ischemic attack, PT-INR = prothrombin time ineternational normalized ratio. †p b 0.05 versus no MR group, ‡p b 0.05 versus mild MR group.
The TEE findings showed that patients with severe MR had higher LAA peak flow velocity (35.2 ± 17.6 cm/s) compared to those with no MR (25.7 ± 14.7 cm/s) and mild MR (25.4 ± 13.8 cm/s) (p b 0.05, Fig. 2). In addition, the severity of LASEC was significantly lower in patients with severe MR (0.7 ± 0.7) compared to those with no MR (1.9 ± 1.3), mild MR (2.2 ± 1.3) and moderate MR (1.7 ± 1.0) (p b 0.05, Fig. 3). Seven percent of patients with no MR had LAA thrombi, while 10.9% of those with mild MR and 8.9% of those with moderate MR had thrombi in their LAA. None of the patients with severe MR had LAA thrombi. However, the difference in the frequency of LAA thrombi did not reach the statistical significance (p value = 0.41). Multiple logistic analysis demonstrated that severe MR was a negative predictor (odds ratio 0.27; 95% confidence interval (CI), 0.09–0.86; p b 0.05) and advanced age was a positive predictor (odds ratio 2.43; 95% CI, 1.30– 4.55; p b 0.01) of dense LASEC (≥grade 3) or reduced LAA flow velocity (≤20 cm/s). D-dimer levels increased as the severity of MR increased, but not for patients with severe MR (Fig. 4). Patients with moderate MR showed significantly higher D-dimer levels (1.72 ± 1.45 µg/ml) compared to those without MR (0.82 ± 1.15 µg/ml), mild MR (0.97 ± 1.09 µg/ml) and severe MR (0.76 ± 0.95 µg/ml) (p b 0.05). There was no difference in D-dimer levels among the different etiologies of MR. 4. Discussion Based on TEE findings and D-dimer levels, patients with nonrheumatic AF who have severe MR would appear to have lower thromboembolic risk than those with mild or moderate MR. This might be due to MR blood stream preventing formation of thrombi in LAA of patients with severe MR. In addition, AF patients with Table 2 Echocardiographic variables. Severity of mitral regurgitation
LAD (mm) LVDd (mm) LVEF (%) Etiology of MR Prolapse Ruptured chordae Tethering Poor coaptation
No
Mild
Moderate
Severe
(n = 114)
(n = 92)
(n = 45)
(n = 20)
40 ± 8 47 ± 9 60 ± 11
45 ± 8† 50 ± 7† 55 ± 13†
49 ± 9† 53 ± 9† 54 ± 16
55 ± 10†‡§ 57 ± 10†‡ 59 ± 10
7(8) 0(0) 4(4) 81(88)
7(16) 0(0) 3(7) 35(78)
9(45) 3(15) 1(5) 7(35)
Values are number of patients (%) or mean ± SD. LAD = left atrial dimension, LVDd = left ventricular diastolic diameter, LVEF = left ventricular ejection fraction. †p b 0.05 versus no MR group, ‡p b 0.05 versus mild MR group, §p b 0.05 versus moderate MR group.
Fig. 2. Relationship between the severity of mitral regurgitation (MR) and left appendage flow velocity. Note the high flow velocity in the severe MR group. Mean ± SD.
moderate MR had increased D-dimer levels when compared to those without MR. AF with heart failure could result in hypercoagulability in the LA via endothelial damage and dysfunction [20]. Thus, the Ddimer levels in patients with MR could be affected not only by the blood flow in LAA but also by clinical risk factors including heart failure and aging. Previous studies showed that TEE findings correlated with stroke risk in patients with nonvalvular AF [21,22]. Reduced LAA flow velocities (LAA peak velocity ≤ 20 cm/s) and dense LASEC have presaged thrombus formation. Significant MR has been reported to prevent blood stasis in the LA cavity and reduce the thromboembolic risk in patients with AF [7,9]. In the present study, patients with severe MR had faint SEC and higher LAA peak flow velocity compared to those with mild MR. The presence of severe MR increased regurgitant volume, thereby reducing SEC but increasing LAA flow velocity, when compared with mild to moderate MR. Our findings are in agreement with previous echocardiographic data of Movsowitz et al. who showed that increased severity of MR decreased the prevalence SEC and thrombi on TEE [9]. However, their study included subject who had sinus rhythm, and only 89 patients with atrial fibrillation were studied [9]. In contrast, we studied a larger number of patients. We studied only patients with permanent AF, because the frequency and duration of AF in patients with paroxysmal AF can affect LAA function. Similar to other studies which showed that plasma levels of Ddimer were increased in patients with nonvalvular AF, [23] we demonstrated in a previous study that increased levels of D-dimer correlated with increased thromboembolic risk [15]. Patients with elevated levels of D-dimer had higher incidence of thromboembolic events [15]. In our study, the levels of D-dimer were higher in patients with moderate MR compared to those with severe MR, suggesting that prevention of LA blood stagnation improved hypercoagulable state, at least in part, in patients with nonrheumatic AF. Fukazawa et al. also found that plasma levels of prothrombin fragment 1 + 2, thrombinantithrombin III complex, and D-dimer were significantly lower in nonrheumatic AF patients who had moderate to severe MR compared to patients without significant MR [5]. However, the number of patients in their study was small and the severity of MR was classified into only 2 groups; i.e., the ‘no MR or mild MR’ group versus ‘moderate to severe MR’ group. Since TEE findings were not available in their study, the precise mechanism for the reduction in the levels of hemostatic markers remains unclear. Miyasaka et al. also reported an increased prevalence of thromboembolic events in patients with mild MR when compared with those with higher grades of MR [11]. In our study, we also found that patients with mild to moderate MR had significantly increased LASEC and D-dimer levels, indicating that these patients were at increased risk of thromboembolism.
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Fig. 3. Relation between the severity of MR and left atrial spontaneous echo contrast (SEC). Note the reduced left atrial SEC in the severe MR group. Mean ± SD.
The presence of severe MR reduced markers of embolic risks, as determined by TEE findings and D-dimer levels, when compared to those with moderate MR. Patients with moderate MR exhibited the highest D-dimer levels among the 4 groups in our current study. The increased thromboembolic risk may be attributable to heart failure in the moderate MR group, since heart failure was identified as a thromboembolic risk factor in previous studies [3]. Therefore, moderate MR does not reduce embolic risk and patients with moderate MR may require intensive anticoagulant therapy. In patients with severe MR, the MR jet may agitate blood stasis in LA cavity, reducing LASEC and increasing LAA blood flow. 4.1. Study limitations Our study is limited by the fact that it retrospectively evaluated thromboembolic risk in patients with MR. Further prospective studies are still needed to reach any definitive conclusion regarding thromboembolic risk in patients with MR. Our choice to include patients on anticoagulant therapy may also have biased our results. Although there were no significant differences in the frequency of warfarin treatment and intensity of anticoagulation (PT-INR) among the 4 patient groups, levels of D-dimer in no MR and mild MR groups were not increased as compared with our previous nonvalvular AF patients who did not receive anticoagulation therapy [15]. In addition, warfarin therapy itself has not been shown to affect the presence and severity of LASEC [24]. Finally, our study may have had a selection bias. Because the study patients underwent TEE for evaluation of potential cardiac source of emboli, our findings would, by necessity, include results from patients at high risk for thromboembolism. The identification of MR grades using color-coded MR signals is also prone to substantial interobserver variability in patients with nonrheumatic AF, possibly due to the irregularity of cardiac cycles. 5. Conclusion The present study suggests that AF patients with severe MR are at lower thromboembolic risk compared to AF patients with mild to moderate MR. In addition, AF patients with moderate MR may have a higher thromboembolic risk. Acknowledgment The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [25].
Fig. 4. Effect of the severity of MR on plasma D-dimer levels. Mean ± SD.
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