- Email: [email protected]
Fate of left atrial thrombi in patients with atrial fibrillation determined by transesophageal echocardiography and cerebral magnetic resonance imaging
Fate of Left Atrial Thrombi in Patients With Atrial Fibrillation Determined by Transesophageal Echocardiography and Cerebral Magnetic Resonance Imaging Peter Bernhardt, MD, Harald Schmidt, MD, Christoph Hammerstingl, MD, Matthias Hackenbroch, MD, Torsten Sommer, MD, Berndt Lüderitz, MD, PhD, and Heyder Omran, MD We screened forty-three patients with atrial fibrillation and left atrial thrombi for the incidence of cerebral embolism and thrombus disappearance by transesophageal echocardiography and cerebral magnetic resonance imaging over a period of 12 months. Patients with left atrial thrombi had an increased risk for cerebral embolism and/or death (16% during a 12-month observation period). Low peak emptying velocities of the left atrial appendage and a history of thromboembolism were predictors of an event. Thrombus disappearance rate under continued oral anticoagulation was 56% during 12 months. Thrombus size and echogenicity may predict thrombus resolution. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;94:801– 804)
e conducted a prospective and serial study (1) to assess the fate of left atrial (LA) thrombi W under continued anticoagulation therapy, (2) to evaluate the incidence of cerebral embolism during a follow-up period of 12 months using serial cranial magnetic resonance imaging (MRI) scanning, and (3) to determine predictors of thrombus disappearance and cerebral embolism. •••
Between 1998 and 2001, all patients ⬎18 years of age with atrial fibrillation and LA thrombi were included in the study. Exclusion criteria were contraindications to cerebral MRI, to transesophageal echocardiography, and to oral anticoagulation and the inability to give written informed consent. Written informed consent was obtained from all patients, and the study was approved by the institutional review board of the University of Bonn. All patients were examined clinically. At the index admission, we assessed cardiovascular risk factors (arterial hypertension, smoking, diabetes mellitus, hypercholesterolemia, family history) and the history of embolism. Twelve-lead surface electrocardiograms were From the Departments of Medicine–Cardiology and Radiology, University of Bonn, Bonn; and St.-Marien-Hospital Bonn, Bonn, Germany. This study was supported by grant BONFOR #0-707 from the University of Bonn, Bonn, Germany. Dr. Bernhardt’s address is: MRT-Center at the St. Gertrauden Hospital Berlin, Paretzer Str. 12, 10713 Berlin, Germany. E-mail: [email protected]. Manuscript received January 15, 2004; revised manuscript received and accepted June 3, 2004. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 September 15, 2004
obtained. During follow-up, patients were examined serially at the index admission and at 1, 3, 6, and 12 months. All studies were conducted with commercially available equipment (Vingmed 800c, System V, GE Medical Systems, Inc., Milwaukee, Wisconsin). For transthoracic echocardiography, a 1.7/3.4-MHz electronic transducer was used. The M-mode LA dimension and left ventricular ejection fraction were measured according to the recommendations of the American Society of Echocardiography.1 Transesophageal echocardiography was performed with a 6.7-MHz multiplane electronic transducer, as previously reported by our study group.2,3 Cineloops of the left atrium and the LA appendage were stored. The sample volume of the pulsed Doppler was placed 1 cm into the orifice of the LA appendage, and the profile of the velocities was recorded. Echocardiographic evaluations were performed by 2 independent observers examining the digitized images after the original examination. The images were displayed in random order without clinical information about the patients and analyzed using the evaluation software provided by the manufacturer (Echopac, GE Medical Systems, Inc.). Interobserver differences were resolved by a third observer. The cineloops of the left atrium and LA appendage were examined for thrombi and spontaneous echo contrast. A thrombus was defined as an echodense intracavitary mass distinct from the underlying endocardium not caused by pectinate muscles. The degree of spontaneous echo contrast was categorized as being either absent (0), mild (1⫹), mild to moderate (2⫹), moderate (3⫹), or severe (4⫹) on the basis of the system described by Fatkin et al.4 LA appendage area and peak emptying velocities were measured as previously reported.2,4 Patients without effective anticoagulation at admission received intravenous weight-adjusted unfractionated heparin 17 U · kg⫺1 · h⫺1 during hospitalization; further dose adjustments were performed to achieve an activated partial thromboplastin time ratio of 1.5 to 2.5 times the control value, which was presumed to be effective. Before discharge, all patients were transferred to oral anticoagulation with phenprocoumon. The effectiveness of anticoagulation was assessed by the international normalized ratio (INR). An INR ⬎2 was defined as the therapeutic range.5,6 The target range of the INR was 2.0 to 3.0 according to the recommendations of the Ameri0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.06.010
801
TABLE 1 Patients’ Characteristics Patients (n ⫽ 43)
Characteristic Age (yrs) Women Previous thromboembolism Diabetes mellitus Smoker Systemic hypertension Hypercholesterolemia (⬎220 mg/dl) Anticoagulation at admission Embolism during follow-up
62.9 ⫾ 9.5 25 (58%) 19 (44%) 7 (16%) 11 (26%) 19 (44%) 23 (53%) 15 (35%) 7 (16%)
TABLE 2 Echocardiographic Data Variable
Patients 3
LA volume (cm ) Left ventricular end-diastolic volume (cm3) Left ventricular ejection fraction (%) Spontaneous echo contrast (grade) LA appendage peak emptying velocity (m/s) Thrombus length (cm) Thrombus width (cm) Echodense thrombus Mobile thrombus
98 ⫾ 45 157 ⫾ 63 51 ⫾ 17 3.0 ⫾ 0.5 0.25 ⫾ 0.08 1.6 ⫾ 0.7 1.0 ⫾ 0.5 28 (65%) 24 (56%)
can College of Cardiology, the American Heart Association, and the European Society of Cardiology Board.7 The MRI examinations were performed with a 1.5-T system (Gyroscan ACS-NT, Philips Medical Systems, Andover, Massachusetts; maximal gradient strength 21 mT/m, increase time 0.2 ms, maximal slew rate 105 T · m⫺1 · s⫺1). The imaging protocol included a diffusion-weighted, single-shot, spin-echo echoplanar sequence (diffusion gradient b values of 0, 500, and 1,000 s/mm2; repetition time 4,000 ms; echo time 120 ms/85 ms; slice thickness 6 mm; matrix 101 ⫻ 256), turbo fluid-attenuated inversion recovery (repetition time 6,000 ms, echo time 100 ms), and T2-weighted turbo spin-echo (repetition time 3,700 ms, echo time 90 ms) sequences. The acquisition time for the diffusionweighted sequences was 36 seconds. Diffusion-weighted images were acquired with diffusion gradients applied in 3 orthogonal directions.8 –11 All MRI studies were evaluated by experienced consultant radiologists blinded to neurologic status and clinical procedure. Magnetic resonance images of the brain were evaluated for the presence of focal diffusion abnormalities (bright lesions in the diffusion-weighted imaging) in a pattern consistent with embolic lesions (i.e., cortical or subcortical localization or in the vascular territory of perforating arteries). Diffuse alterations in the diffusion-weighted imaging or patterns of watershed ischemia were not considered to be embolic types of lesions. The number, size (⬍5, 5 to 10, and ⬎10 mm), and vascular territory of all focal diffusion abnormalities were recorded. In patients who showed focal diffusion abnormalities, follow-up MRI investigations including T2weighted turbo fluid-attenuated inversion recovery 802 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 94
FIGURE 1. Kaplan-Meier survival graph showing thrombus persistence during the 12-month observation period.
FIGURE 2. Kaplan-Meier survival graph presenting cerebral embolism as demonstrated by MRI during 1-year follow-up.
and turbo spin-echo sequences were performed after 3 months to define the presence or absence of subsequent infarcts at the locations of the diffusion abnormalities. All patients underwent neurologic assessment by a board-certified neurologists. A neurologic complication was defined as any new cranial nerve, motor, or sensory deficiency, reflex change, pyramidal sign, or occurrence of mental alteration. All patients underwent ultrasound examination of the carotids and of the aorta (HDI 3000, ATL Ultrasound, Inc., Bothell, Washington) at the index admission. Considering all information from B-mode, colorDoppler, and Doppler ultrasound, stenoses of the common or the internal carotid artery were measured as reductions of the luminal area according to established criteria.12 All patients with stenoses ⬎50% were excluded from the study. Data are reported as means ⫾ SDs. Continuous variables between groups were compared using t tests for unpaired observations. Nominal data were compared using Fisher’s exact test. Categorical data were compared using the Wilcoxon signed rank test for SEPTEMBER 15, 2004
(56%) disappeared: 16% at 1 month, 42% at 3 months, 49% at 6 months, Patients With Patients Without and 56% at 12 months (Figure 1). Variable Thrombus Resolution Thrombus Resolution Thrombus size in patients without thrombus disappearance decreased 83 ⫾ 27* 116 ⫾ 55* LA volume (cm3) Left ventricular end-diastolic volume (cm3) 163 ⫾ 59 149 ⫾ 68 from 1.9 ⫾ 0.6 cm in length and 1.3 Left ventricular ejection fraction (%) 54 ⫾ 12 47 ⫾ 21 ⫾ 0.4 cm in width to 1.4 ⫾ 0.6 cm in Spontaneous echo contrast (grade) 3.1 ⫾ 0.6 2.9 ⫾ 0.5 length and 0.8 ⫾ 0.5 cm in width. LA appendage peak emptying velocity (m/s) 0.24 ⫾ 0.08 0.26 ⫾ 0.08 Patients with persistent thrombi had Thrombus length (cm) 1.5 ⫾ 0.8† 1.9 ⫾ 0.6† Thrombus width (cm) 0.8 ⫾ 0.5† 1.3 ⫾ 0.4† less frequent echodense thrombi afEchodense thrombus 11 (46%) 17 (89%) ter the 12-month follow-up period Mobile thrombus 14 (58%) 10 (53%) (17 [89%] at index admission com*p ⬍0.05; †thrombus size (length ⫻ width) p ⬍0.05. pared with 12 [63%] at the end of the observation period). Nine patients had old focal diffusion abnormalities at the index adTABLE 4 Patients With and Without Embolism mission. During the 12-month follow-up, 16% of the patients (7 of 43) Patients With Patients Without Variable Embolism Embolism manifested acute cerebral diffusion abnormalities in a pattern consistent 91 ⫾ 49 100 ⫾ 45 LA volume (cm3) with embolic lesions. The size of the Left ventricular end-diastolic volume (cm3) 183 ⫾ 24 152 ⫾ 67 Left ventricular ejection fraction (%) 48 ⫾ 21 52 ⫾ 16 embolic lesions was ⬍5 mm in 5 Spontaneous echo contrast (grade) 3.0 ⫾ 0.6 3.0 ⫾ 0.6 lesions, 5 to 10 mm in 1 lesion, and Left atrial appendage peak emptying velocity (m/s) 0.33 ⫾ 0.08* 0.23 ⫾ 0.07* ⬎10 mm in 1 lesion. The affected Thrombus length (cm) 2.1 ⫾ 0.7 1.5 ⫾ 0.7 vascular territories were superficial Thrombus width (cm) 1.2 ⫾ 0.6 1.0 ⫾ 0.5 Echodense thrombus 5 (71%) 21 (58%) middle cerebral arteries (n ⫽ 5) and Mobile thrombus 4 (57%) 20 (56%) deep middle cerebral arteries (n ⫽ 2). No diffusion abnormalities in *p ⬍0.01. border zone areas or diffuse diffusion abnormalities were noted. Three matched pairs. In all cases, a p value ⬍0.05 was of 43 patients (7%) had new MRI findings at the considered statistically significant. Ninety-five percent 1-month follow-up, 5 (12%) at the 3-month follow-up, confidence intervals are given. Logistic regression and 7 (16%) at the 6-month follow-up (Figure 2). analysis was performed to evaluate predictors of Patients with and without anticoagulation before study enrollment did not differ with regard to events during thrombus resolution and cerebral embolism. Fifty-two patients with LA thrombi were screened for follow-up. Six patients had clinically apparent neurologic defenrollment into the study. Nine patients with thrombi were excluded because of pacemaker insertion, inability icits and cerebral infarctions as documented by cranial to conduct follow-up visits, aortic plaques ⬎4 mm, MRI. One patient had clinically silent cerebral emboand/or carotid artery stenosis ⬎50%. Forty-three patients lism as documented by diffusion defects. In the latter formed the study group. Patients’ data are provided in patient, follow-up conventional MRI was performed Table 1. Twenty-three patients (53%) with LA thrombi after 3 months. The patient developed a focal signal received oral anticoagulation therapy with phenprocou- hyperattenuation on the T2-weighted and fluid-attenmon before inclusion in the study. Nineteen patients uated inversion recovery imaging in the region corre(44%) had a history of embolisms. Nine of the patients sponding to the original index lesion, indicating in(21%) had neurologic deficits at admission. All patients farcted brain tissue. Eight patients had carotid stenosis of ⬍50%. Six of had documented permanent atrial fibrillation, as shown by 12-lead surface electrocardiograms obtained during them had thrombus disappearance during follow-up. One patient had a cerebral lesion during the observafollow-up. Measurements of left ventricular and atrial dimen- tion period. Twenty three patients (53%) were anticoagulated sions, left ventricular ejection fractions, and LA appendage peak emptying velocities are given in Table effectively at index admission. Fifteen patients with 2. At the index admission, the mean thrombi dimen- effective anticoagulation at the admission had thrombi sions were 1.6 ⫾ 0.7 cm in length and 1.0 ⫾ 0.5 cm resolution, and 1 patient had a cerebral embolism in width. All thrombi were located in the LA append- during follow-up. During the observation period, the age. Twenty-four thrombi were mobile, 28 were average INR was 2.2 ⫾ 0.4. Patients with and without echodense, and 1 protruded into the left atrium. Spon- effective oral anticoagulation therapy did not differ in taneous echo contrast was present in all cases. Thir- the incidence of embolism (p ⫽ 0.24). The mean INR teen patients had patent foramen ovale. Thirty-nine was 2.3 ⫾ 0.4 before the occurrence of embolic events patients had aortic plaques ⬍4 mm. None of the and 2.2 ⫾ 0.3 at the time of events. Clinical risk factors did not differ between patients patients had mobile aortic atheroma. During the follow-up of 12 months, 24 thrombi with and without thrombus disappearance. Patients with TABLE 3 Patients With and Without Thrombus Resolution
BRIEF REPORTS
803
and without resolution did not differ in left ventricular dimensions (p ⫽ 0.48), left ventricular ejection fractions (p ⫽ 0.17), thrombus mobility (p ⫽ 0.71), patent foramen ovale (p ⫽ 0.45), and spontaneous echo contrast (p ⫽ 0.37) (Table 3). However, patients with thrombus disappearance during the observation period had smaller thrombi (1.5 ⫾ 0.8 cm in length and 0.8 ⫾ 0.5 cm in width vs 1.9 ⫾ 0.6 cm in length and 1.3 ⫾ 0.4 cm in width, p ⫽ 0.04), reduced echogenicity of thrombi (11 [46%] vs 17 [89%], p ⬍0.01), and smaller LA volume (83 ⫾ 27 vs 116 ⫾ 55 cm3, p ⫽ 0.02). Patients with cerebral embolism had significantly greater peak emptying velocities of the LA appendage (31 ⫾ 8 vs 23 ⫾ 7 cm/s, p ⬍0.01) and more commonly had a history of thromboembolic events (5 [71%] vs 9 [25%], p ⫽ 0.02). Patients with effective anticoagulation at the index admission had significantly less frequent embolic events than patients who began anticoagulation at entry into the study (p ⫽ 0.02) (see Table 4). •••
This is the first study to assess the incidence of clinically apparent and silent cerebral embolism with modern MRI techniques in patients with LA thrombi during a 12-month follow-up period. Recent studies have shown that diffusion-weighted cranial MRI may serve as a useful surrogate end point for ischemic stroke.8 –11 Cranial MRI examinations are suited to objectively and quantitatively monitor thromboembolism in patients with atrial thrombi. Continued effective anticoagulation does not prevent thromboembolic events in patients with permanent AF and prevalent LA thrombi. In our study, embolism occurred even in patients with effective anticoagulation (16%). Patients with persistent thrombi should be observed closely.
804 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 94
1. Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp RL, Sahn DJ,
Schiller NB, Tajik A, Teichholz LE, et al. Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two-dimensional Echocardiography. Circulation 1980;62:212–215. 2. Omran H, Jung W, Rabahieh R, Schimpf R, Wolpert C, Hagendorff A, Fehske W, Luderitz B. Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study. J Am Coll Cardiol 1997;29:131–138. 3. Omran H, Jung W, Schimpf R, MacCarter D, Rabahieh R, Wolpert C, Illien S, Luderitz B. Echocardiographic parameters for predicting maintenance of sinus rhythm after internal atrial defibrillation. Am J Cardiol 1998;81:1446 –1449. 4. 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. 5. Laupacis A, Albers G, Dalen J, Dunn MI, Jacobson AK, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 1998;114(suppl):579S–589S. 6. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019 –1026. 7. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, et al, American College of Cardiology/ American Heart Association/European Society of Cardiology Board. ACC/AHA/ ESC guidelines for the management of patients with atrial fibrillation: executive summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 2001;38:1231–1266. 8. Moseley ME, Kucharczyk J, Mintorovitch J, Cohen Y, Kurhanewicz J, Derugin N, Asgari H, Norman D. Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats. Am J Neuroradiol 1990;11:423– 429. 9. Warach S, Gaa J, Siewert B, Wielopolski P, Edelman RR. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 1995;37:231–241. 10. Schaefer PW, Grant PE, Gonzalez G. Diffusion-weighted MR imaging of the brain. Radiology 2000;217:331–345. 11. Omran H, Schmidt H, Hackenbroch M, Illien S, Bernhardt P, von der Recke G, Fimmers R, Flacke S, Layer G, Pohl C, et al. Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study. Lancet 2003;361:1241–1246. 12. Landwehr P, Schulte O, Voshage G. Ultrasound examination of carotid and vertebral arteries. Eur Radiol 2001;11:1521–1534.
SEPTEMBER 15, 2004
e conducted a prospective and serial study (1) to assess the fate of left atrial (LA) thrombi W under continued anticoagulation therapy, (2) to evaluate the incidence of cerebral embolism during a follow-up period of 12 months using serial cranial magnetic resonance imaging (MRI) scanning, and (3) to determine predictors of thrombus disappearance and cerebral embolism. •••
Between 1998 and 2001, all patients ⬎18 years of age with atrial fibrillation and LA thrombi were included in the study. Exclusion criteria were contraindications to cerebral MRI, to transesophageal echocardiography, and to oral anticoagulation and the inability to give written informed consent. Written informed consent was obtained from all patients, and the study was approved by the institutional review board of the University of Bonn. All patients were examined clinically. At the index admission, we assessed cardiovascular risk factors (arterial hypertension, smoking, diabetes mellitus, hypercholesterolemia, family history) and the history of embolism. Twelve-lead surface electrocardiograms were From the Departments of Medicine–Cardiology and Radiology, University of Bonn, Bonn; and St.-Marien-Hospital Bonn, Bonn, Germany. This study was supported by grant BONFOR #0-707 from the University of Bonn, Bonn, Germany. Dr. Bernhardt’s address is: MRT-Center at the St. Gertrauden Hospital Berlin, Paretzer Str. 12, 10713 Berlin, Germany. E-mail: [email protected]. Manuscript received January 15, 2004; revised manuscript received and accepted June 3, 2004. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 94 September 15, 2004
obtained. During follow-up, patients were examined serially at the index admission and at 1, 3, 6, and 12 months. All studies were conducted with commercially available equipment (Vingmed 800c, System V, GE Medical Systems, Inc., Milwaukee, Wisconsin). For transthoracic echocardiography, a 1.7/3.4-MHz electronic transducer was used. The M-mode LA dimension and left ventricular ejection fraction were measured according to the recommendations of the American Society of Echocardiography.1 Transesophageal echocardiography was performed with a 6.7-MHz multiplane electronic transducer, as previously reported by our study group.2,3 Cineloops of the left atrium and the LA appendage were stored. The sample volume of the pulsed Doppler was placed 1 cm into the orifice of the LA appendage, and the profile of the velocities was recorded. Echocardiographic evaluations were performed by 2 independent observers examining the digitized images after the original examination. The images were displayed in random order without clinical information about the patients and analyzed using the evaluation software provided by the manufacturer (Echopac, GE Medical Systems, Inc.). Interobserver differences were resolved by a third observer. The cineloops of the left atrium and LA appendage were examined for thrombi and spontaneous echo contrast. A thrombus was defined as an echodense intracavitary mass distinct from the underlying endocardium not caused by pectinate muscles. The degree of spontaneous echo contrast was categorized as being either absent (0), mild (1⫹), mild to moderate (2⫹), moderate (3⫹), or severe (4⫹) on the basis of the system described by Fatkin et al.4 LA appendage area and peak emptying velocities were measured as previously reported.2,4 Patients without effective anticoagulation at admission received intravenous weight-adjusted unfractionated heparin 17 U · kg⫺1 · h⫺1 during hospitalization; further dose adjustments were performed to achieve an activated partial thromboplastin time ratio of 1.5 to 2.5 times the control value, which was presumed to be effective. Before discharge, all patients were transferred to oral anticoagulation with phenprocoumon. The effectiveness of anticoagulation was assessed by the international normalized ratio (INR). An INR ⬎2 was defined as the therapeutic range.5,6 The target range of the INR was 2.0 to 3.0 according to the recommendations of the Ameri0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2004.06.010
801
TABLE 1 Patients’ Characteristics Patients (n ⫽ 43)
Characteristic Age (yrs) Women Previous thromboembolism Diabetes mellitus Smoker Systemic hypertension Hypercholesterolemia (⬎220 mg/dl) Anticoagulation at admission Embolism during follow-up
62.9 ⫾ 9.5 25 (58%) 19 (44%) 7 (16%) 11 (26%) 19 (44%) 23 (53%) 15 (35%) 7 (16%)
TABLE 2 Echocardiographic Data Variable
Patients 3
LA volume (cm ) Left ventricular end-diastolic volume (cm3) Left ventricular ejection fraction (%) Spontaneous echo contrast (grade) LA appendage peak emptying velocity (m/s) Thrombus length (cm) Thrombus width (cm) Echodense thrombus Mobile thrombus
98 ⫾ 45 157 ⫾ 63 51 ⫾ 17 3.0 ⫾ 0.5 0.25 ⫾ 0.08 1.6 ⫾ 0.7 1.0 ⫾ 0.5 28 (65%) 24 (56%)
can College of Cardiology, the American Heart Association, and the European Society of Cardiology Board.7 The MRI examinations were performed with a 1.5-T system (Gyroscan ACS-NT, Philips Medical Systems, Andover, Massachusetts; maximal gradient strength 21 mT/m, increase time 0.2 ms, maximal slew rate 105 T · m⫺1 · s⫺1). The imaging protocol included a diffusion-weighted, single-shot, spin-echo echoplanar sequence (diffusion gradient b values of 0, 500, and 1,000 s/mm2; repetition time 4,000 ms; echo time 120 ms/85 ms; slice thickness 6 mm; matrix 101 ⫻ 256), turbo fluid-attenuated inversion recovery (repetition time 6,000 ms, echo time 100 ms), and T2-weighted turbo spin-echo (repetition time 3,700 ms, echo time 90 ms) sequences. The acquisition time for the diffusionweighted sequences was 36 seconds. Diffusion-weighted images were acquired with diffusion gradients applied in 3 orthogonal directions.8 –11 All MRI studies were evaluated by experienced consultant radiologists blinded to neurologic status and clinical procedure. Magnetic resonance images of the brain were evaluated for the presence of focal diffusion abnormalities (bright lesions in the diffusion-weighted imaging) in a pattern consistent with embolic lesions (i.e., cortical or subcortical localization or in the vascular territory of perforating arteries). Diffuse alterations in the diffusion-weighted imaging or patterns of watershed ischemia were not considered to be embolic types of lesions. The number, size (⬍5, 5 to 10, and ⬎10 mm), and vascular territory of all focal diffusion abnormalities were recorded. In patients who showed focal diffusion abnormalities, follow-up MRI investigations including T2weighted turbo fluid-attenuated inversion recovery 802 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 94
FIGURE 1. Kaplan-Meier survival graph showing thrombus persistence during the 12-month observation period.
FIGURE 2. Kaplan-Meier survival graph presenting cerebral embolism as demonstrated by MRI during 1-year follow-up.
and turbo spin-echo sequences were performed after 3 months to define the presence or absence of subsequent infarcts at the locations of the diffusion abnormalities. All patients underwent neurologic assessment by a board-certified neurologists. A neurologic complication was defined as any new cranial nerve, motor, or sensory deficiency, reflex change, pyramidal sign, or occurrence of mental alteration. All patients underwent ultrasound examination of the carotids and of the aorta (HDI 3000, ATL Ultrasound, Inc., Bothell, Washington) at the index admission. Considering all information from B-mode, colorDoppler, and Doppler ultrasound, stenoses of the common or the internal carotid artery were measured as reductions of the luminal area according to established criteria.12 All patients with stenoses ⬎50% were excluded from the study. Data are reported as means ⫾ SDs. Continuous variables between groups were compared using t tests for unpaired observations. Nominal data were compared using Fisher’s exact test. Categorical data were compared using the Wilcoxon signed rank test for SEPTEMBER 15, 2004
(56%) disappeared: 16% at 1 month, 42% at 3 months, 49% at 6 months, Patients With Patients Without and 56% at 12 months (Figure 1). Variable Thrombus Resolution Thrombus Resolution Thrombus size in patients without thrombus disappearance decreased 83 ⫾ 27* 116 ⫾ 55* LA volume (cm3) Left ventricular end-diastolic volume (cm3) 163 ⫾ 59 149 ⫾ 68 from 1.9 ⫾ 0.6 cm in length and 1.3 Left ventricular ejection fraction (%) 54 ⫾ 12 47 ⫾ 21 ⫾ 0.4 cm in width to 1.4 ⫾ 0.6 cm in Spontaneous echo contrast (grade) 3.1 ⫾ 0.6 2.9 ⫾ 0.5 length and 0.8 ⫾ 0.5 cm in width. LA appendage peak emptying velocity (m/s) 0.24 ⫾ 0.08 0.26 ⫾ 0.08 Patients with persistent thrombi had Thrombus length (cm) 1.5 ⫾ 0.8† 1.9 ⫾ 0.6† Thrombus width (cm) 0.8 ⫾ 0.5† 1.3 ⫾ 0.4† less frequent echodense thrombi afEchodense thrombus 11 (46%) 17 (89%) ter the 12-month follow-up period Mobile thrombus 14 (58%) 10 (53%) (17 [89%] at index admission com*p ⬍0.05; †thrombus size (length ⫻ width) p ⬍0.05. pared with 12 [63%] at the end of the observation period). Nine patients had old focal diffusion abnormalities at the index adTABLE 4 Patients With and Without Embolism mission. During the 12-month follow-up, 16% of the patients (7 of 43) Patients With Patients Without Variable Embolism Embolism manifested acute cerebral diffusion abnormalities in a pattern consistent 91 ⫾ 49 100 ⫾ 45 LA volume (cm3) with embolic lesions. The size of the Left ventricular end-diastolic volume (cm3) 183 ⫾ 24 152 ⫾ 67 Left ventricular ejection fraction (%) 48 ⫾ 21 52 ⫾ 16 embolic lesions was ⬍5 mm in 5 Spontaneous echo contrast (grade) 3.0 ⫾ 0.6 3.0 ⫾ 0.6 lesions, 5 to 10 mm in 1 lesion, and Left atrial appendage peak emptying velocity (m/s) 0.33 ⫾ 0.08* 0.23 ⫾ 0.07* ⬎10 mm in 1 lesion. The affected Thrombus length (cm) 2.1 ⫾ 0.7 1.5 ⫾ 0.7 vascular territories were superficial Thrombus width (cm) 1.2 ⫾ 0.6 1.0 ⫾ 0.5 Echodense thrombus 5 (71%) 21 (58%) middle cerebral arteries (n ⫽ 5) and Mobile thrombus 4 (57%) 20 (56%) deep middle cerebral arteries (n ⫽ 2). No diffusion abnormalities in *p ⬍0.01. border zone areas or diffuse diffusion abnormalities were noted. Three matched pairs. In all cases, a p value ⬍0.05 was of 43 patients (7%) had new MRI findings at the considered statistically significant. Ninety-five percent 1-month follow-up, 5 (12%) at the 3-month follow-up, confidence intervals are given. Logistic regression and 7 (16%) at the 6-month follow-up (Figure 2). analysis was performed to evaluate predictors of Patients with and without anticoagulation before study enrollment did not differ with regard to events during thrombus resolution and cerebral embolism. Fifty-two patients with LA thrombi were screened for follow-up. Six patients had clinically apparent neurologic defenrollment into the study. Nine patients with thrombi were excluded because of pacemaker insertion, inability icits and cerebral infarctions as documented by cranial to conduct follow-up visits, aortic plaques ⬎4 mm, MRI. One patient had clinically silent cerebral emboand/or carotid artery stenosis ⬎50%. Forty-three patients lism as documented by diffusion defects. In the latter formed the study group. Patients’ data are provided in patient, follow-up conventional MRI was performed Table 1. Twenty-three patients (53%) with LA thrombi after 3 months. The patient developed a focal signal received oral anticoagulation therapy with phenprocou- hyperattenuation on the T2-weighted and fluid-attenmon before inclusion in the study. Nineteen patients uated inversion recovery imaging in the region corre(44%) had a history of embolisms. Nine of the patients sponding to the original index lesion, indicating in(21%) had neurologic deficits at admission. All patients farcted brain tissue. Eight patients had carotid stenosis of ⬍50%. Six of had documented permanent atrial fibrillation, as shown by 12-lead surface electrocardiograms obtained during them had thrombus disappearance during follow-up. One patient had a cerebral lesion during the observafollow-up. Measurements of left ventricular and atrial dimen- tion period. Twenty three patients (53%) were anticoagulated sions, left ventricular ejection fractions, and LA appendage peak emptying velocities are given in Table effectively at index admission. Fifteen patients with 2. At the index admission, the mean thrombi dimen- effective anticoagulation at the admission had thrombi sions were 1.6 ⫾ 0.7 cm in length and 1.0 ⫾ 0.5 cm resolution, and 1 patient had a cerebral embolism in width. All thrombi were located in the LA append- during follow-up. During the observation period, the age. Twenty-four thrombi were mobile, 28 were average INR was 2.2 ⫾ 0.4. Patients with and without echodense, and 1 protruded into the left atrium. Spon- effective oral anticoagulation therapy did not differ in taneous echo contrast was present in all cases. Thir- the incidence of embolism (p ⫽ 0.24). The mean INR teen patients had patent foramen ovale. Thirty-nine was 2.3 ⫾ 0.4 before the occurrence of embolic events patients had aortic plaques ⬍4 mm. None of the and 2.2 ⫾ 0.3 at the time of events. Clinical risk factors did not differ between patients patients had mobile aortic atheroma. During the follow-up of 12 months, 24 thrombi with and without thrombus disappearance. Patients with TABLE 3 Patients With and Without Thrombus Resolution
BRIEF REPORTS
803
and without resolution did not differ in left ventricular dimensions (p ⫽ 0.48), left ventricular ejection fractions (p ⫽ 0.17), thrombus mobility (p ⫽ 0.71), patent foramen ovale (p ⫽ 0.45), and spontaneous echo contrast (p ⫽ 0.37) (Table 3). However, patients with thrombus disappearance during the observation period had smaller thrombi (1.5 ⫾ 0.8 cm in length and 0.8 ⫾ 0.5 cm in width vs 1.9 ⫾ 0.6 cm in length and 1.3 ⫾ 0.4 cm in width, p ⫽ 0.04), reduced echogenicity of thrombi (11 [46%] vs 17 [89%], p ⬍0.01), and smaller LA volume (83 ⫾ 27 vs 116 ⫾ 55 cm3, p ⫽ 0.02). Patients with cerebral embolism had significantly greater peak emptying velocities of the LA appendage (31 ⫾ 8 vs 23 ⫾ 7 cm/s, p ⬍0.01) and more commonly had a history of thromboembolic events (5 [71%] vs 9 [25%], p ⫽ 0.02). Patients with effective anticoagulation at the index admission had significantly less frequent embolic events than patients who began anticoagulation at entry into the study (p ⫽ 0.02) (see Table 4). •••
This is the first study to assess the incidence of clinically apparent and silent cerebral embolism with modern MRI techniques in patients with LA thrombi during a 12-month follow-up period. Recent studies have shown that diffusion-weighted cranial MRI may serve as a useful surrogate end point for ischemic stroke.8 –11 Cranial MRI examinations are suited to objectively and quantitatively monitor thromboembolism in patients with atrial thrombi. Continued effective anticoagulation does not prevent thromboembolic events in patients with permanent AF and prevalent LA thrombi. In our study, embolism occurred even in patients with effective anticoagulation (16%). Patients with persistent thrombi should be observed closely.
804 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 94
1. Henry WL, DeMaria A, Gramiak R, King DL, Kisslo JA, Popp RL, Sahn DJ,
Schiller NB, Tajik A, Teichholz LE, et al. Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two-dimensional Echocardiography. Circulation 1980;62:212–215. 2. Omran H, Jung W, Rabahieh R, Schimpf R, Wolpert C, Hagendorff A, Fehske W, Luderitz B. Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study. J Am Coll Cardiol 1997;29:131–138. 3. Omran H, Jung W, Schimpf R, MacCarter D, Rabahieh R, Wolpert C, Illien S, Luderitz B. Echocardiographic parameters for predicting maintenance of sinus rhythm after internal atrial defibrillation. Am J Cardiol 1998;81:1446 –1449. 4. 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. 5. Laupacis A, Albers G, Dalen J, Dunn MI, Jacobson AK, Singer DE. Antithrombotic therapy in atrial fibrillation. Chest 1998;114(suppl):579S–589S. 6. Hylek EM, Go AS, Chang Y, Jensvold NG, Henault LE, Selby JV, Singer DE. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019 –1026. 7. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, et al, American College of Cardiology/ American Heart Association/European Society of Cardiology Board. ACC/AHA/ ESC guidelines for the management of patients with atrial fibrillation: executive summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 2001;38:1231–1266. 8. Moseley ME, Kucharczyk J, Mintorovitch J, Cohen Y, Kurhanewicz J, Derugin N, Asgari H, Norman D. Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats. Am J Neuroradiol 1990;11:423– 429. 9. Warach S, Gaa J, Siewert B, Wielopolski P, Edelman RR. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 1995;37:231–241. 10. Schaefer PW, Grant PE, Gonzalez G. Diffusion-weighted MR imaging of the brain. Radiology 2000;217:331–345. 11. Omran H, Schmidt H, Hackenbroch M, Illien S, Bernhardt P, von der Recke G, Fimmers R, Flacke S, Layer G, Pohl C, et al. Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study. Lancet 2003;361:1241–1246. 12. Landwehr P, Schulte O, Voshage G. Ultrasound examination of carotid and vertebral arteries. Eur Radiol 2001;11:1521–1534.
SEPTEMBER 15, 2004