Fate of Left Atrial Thrombi in Patients With AtrialFibrillation Determined by TransesophagealEchocardiography 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 fibrilla-tion and left atrial thrombi for the incidence of cere-bral embolism and thrombus disappearance bytransesophageal echocardiography and cerebralmagnetic resonance imaging over a period of 12months. Patients with left atrial thrombi had an in-creased risk for cerebral embolism and/or death(16% during a 12-month observation period). Lowpeak emptying velocities of the left atrial appendageand a history of thromboembolism were predictors ofan event. Thrombus disappearance rate under con-tinued oral anticoagulation was 56% during 12months. Thrombus size and echogenicity may predictthrombus resolution. �2004 by Excerpta Medica,Inc.

(Am J Cardiol 2004;94:801–804)

We conducted a prospective and serial study (1)to assess the fate of left atrial (LA) thrombi

under continued anticoagulation therapy, (2) to eval-uate the incidence of cerebral embolism during afollow-up period of 12 months using serial cranialmagnetic resonance imaging (MRI) scanning, and (3)to determine predictors of thrombus disappearanceand cerebral embolism.

• • •Between 1998 and 2001, all patients �18 years of

age with atrial fibrillation and LA thrombi were in-cluded in the study. Exclusion criteria were contrain-dications to cerebral MRI, to transesophageal echo-cardiography, and to oral anticoagulation and theinability to give written informed consent. Writteninformed consent was obtained from all patients, andthe study was approved by the institutional reviewboard of the University of Bonn.

All patients were examined clinically. At the indexadmission, we assessed cardiovascular risk factors (arte-rial hypertension, smoking, diabetes mellitus, hypercho-lesterolemia, family history) and the history of embo-lism. Twelve-lead surface electrocardiograms were

obtained. During follow-up, patients were examined se-rially at the index admission and at 1, 3, 6, and 12months.

All studies were conducted with commerciallyavailable equipment (Vingmed 800c, System V, GEMedical Systems, Inc., Milwaukee, Wisconsin). Fortransthoracic echocardiography, a 1.7/3.4-MHz elec-tronic transducer was used. The M-mode LA dimen-sion and left ventricular ejection fraction were mea-sured according to the recommendations of theAmerican Society of Echocardiography.1

Transesophageal echocardiography was performedwith a 6.7-MHz multiplane electronic transducer, aspreviously reported by our study group.2,3 Cineloopsof the left atrium and the LA appendage were stored.The sample volume of the pulsed Doppler was placed1 cm into the orifice of the LA appendage, and theprofile of the velocities was recorded.

Echocardiographic evaluations were performed by2 independent observers examining the digitized im-ages after the original examination. The images weredisplayed in random order without clinical informa-tion about the patients and analyzed using the evalu-ation software provided by the manufacturer(Echopac, GE Medical Systems, Inc.). Interobserverdifferences were resolved by a third observer.

The cineloops of the left atrium and LA appendagewere examined for thrombi and spontaneous echocontrast. A thrombus was defined as an echodenseintracavitary mass distinct from the underlying endo-cardium not caused by pectinate muscles. The degreeof spontaneous echo contrast was categorized as beingeither absent (0), mild (1�), mild to moderate (2�),moderate (3�), or severe (4�) on the basis of thesystem described by Fatkin et al.4 LA appendage areaand peak emptying velocities were measured as pre-viously reported.2,4

Patients without effective anticoagulation at admis-sion received intravenous weight-adjusted unfractionatedheparin 17 U · kg�1 · h�1 during hospitalization; furtherdose adjustments were performed to achieve an activatedpartial thromboplastin time ratio of 1.5 to 2.5 times thecontrol value, which was presumed to be effective. Be-fore discharge, all patients were transferred to oral anti-coagulation with phenprocoumon. The effectiveness ofanticoagulation was assessed by the international nor-malized ratio (INR). An INR �2 was defined as thetherapeutic range.5,6 The target range of the INR was 2.0to 3.0 according to the recommendations of the Ameri-

From the Departments of Medicine–Cardiology and Radiology, Uni-versity of Bonn, Bonn; and St.-Marien-Hospital Bonn, Bonn, Germany.This study was supported by grant BONFOR #0-707 from the Univer-sity of Bonn, Bonn, Germany. Dr. Bernhardt’s address is: MRT-Centerat the St. Gertrauden Hospital Berlin, Paretzer Str. 12, 10713 Berlin,Germany. E-mail: bernhardt@cardiomrt.de. Manuscript received Jan-uary 15, 2004; revised manuscript received and accepted June 3,2004.

801©2004 by Excerpta Medica, Inc. All rights reserved. 0002-9149/04/$–see front matterThe American Journal of Cardiology Vol. 94 September 15, 2004 doi:10.1016/j.amjcard.2004.06.010

can College of Cardiology, the American Heart Associ-ation, and the European Society of Cardiology Board.7

The MRI examinations were performed with a1.5-T system (Gyroscan ACS-NT, Philips MedicalSystems, Andover, Massachusetts; maximal gradi-ent strength 21 mT/m, increase time 0.2 ms, maxi-mal slew rate 105 T · m�1 · s�1). The imaging pro-tocol included a diffusion-weighted, single-shot,spin-echo echoplanar sequence (diffusion gradientb values of 0, 500, and 1,000 s/mm2; repetition time4,000 ms; echo time 120 ms/85 ms; slice thickness6 mm; matrix 101 � 256), turbo fluid-attenuatedinversion recovery (repetition time 6,000 ms, echotime 100 ms), and T2-weighted turbo spin-echo(repetition time 3,700 ms, echo time 90 ms) se-quences. The acquisition time for the diffusion-weighted sequences was 36 seconds.

Diffusion-weighted images were acquired with diffu-sion gradients applied in 3 orthogonal directions.8–11 AllMRI studies were evaluated by experienced consultantradiologists blinded to neurologic status and clinical pro-cedure. Magnetic resonance images of the brain wereevaluated for the presence of focal diffusion abnormali-ties (bright lesions in the diffusion-weighted imaging) ina pattern consistent with embolic lesions (i.e., corticalor subcortical localization or in the vascular territoryof perforating arteries). Diffuse alterations in the dif-fusion-weighted imaging or patterns of watershedischemia were not considered to be embolic types oflesions. The number, size (�5, 5 to 10, and �10 mm),and vascular territory of all focal diffusion abnormal-ities were recorded.

In patients who showed focal diffusion abnormal-ities, follow-up MRI investigations including T2-weighted turbo fluid-attenuated inversion recovery

and turbo spin-echo sequences were performed after 3months to define the presence or absence of subse-quent infarcts at the locations of the diffusion abnor-malities.

All patients underwent neurologic assessment by aboard-certified neurologists. A neurologic complica-tion was defined as any new cranial nerve, motor, orsensory deficiency, reflex change, pyramidal sign, oroccurrence of mental alteration.

All patients underwent ultrasound examination ofthe carotids and of the aorta (HDI 3000, ATL Ultra-sound, Inc., Bothell, Washington) at the index admis-sion. Considering all information from B-mode, color-Doppler, and Doppler ultrasound, stenoses of thecommon or the internal carotid artery were measuredas reductions of the luminal area according to estab-lished criteria.12 All patients with stenoses �50%were excluded from the study.

Data are reported as means � SDs. Continuousvariables between groups were compared using t testsfor unpaired observations. Nominal data were com-pared using Fisher’s exact test. Categorical data werecompared using the Wilcoxon signed rank test for

FIGURE 1. Kaplan-Meier survival graph showing thrombus per-sistence during the 12-month observation period.

FIGURE 2. Kaplan-Meier survival graph presenting cerebral em-bolism as demonstrated by MRI during 1-year follow-up.

TABLE 1 Patients’ Characteristics

CharacteristicPatients(n � 43)

Age (yrs) 62.9 � 9.5Women 25 (58%)Previous thromboembolism 19 (44%)Diabetes mellitus 7 (16%)Smoker 11 (26%)Systemic hypertension 19 (44%)Hypercholesterolemia (�220 mg/dl) 23 (53%)Anticoagulation at admission 15 (35%)Embolism during follow-up 7 (16%)

TABLE 2 Echocardiographic Data

Variable Patients

LA volume (cm3) 98 � 45Left ventricular end-diastolic volume (cm3) 157 � 63Left ventricular ejection fraction (%) 51 � 17Spontaneous echo contrast (grade) 3.0 � 0.5LA appendage peak emptying velocity (m/s) 0.25 � 0.08Thrombus length (cm) 1.6 � 0.7Thrombus width (cm) 1.0 � 0.5Echodense thrombus 28 (65%)Mobile thrombus 24 (56%)

802 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 94 SEPTEMBER 15, 2004

matched pairs. In all cases, a p value �0.05 wasconsidered statistically significant. Ninety-five percentconfidence intervals are given. Logistic regressionanalysis was performed to evaluate predictors ofthrombus resolution and cerebral embolism.

Fifty-two patients with LA thrombi were screened forenrollment into the study. Nine patients with thrombiwere excluded because of pacemaker insertion, inabilityto conduct follow-up visits, aortic plaques �4 mm,and/or carotid artery stenosis �50%. Forty-three patientsformed the study group. Patients’ data are provided inTable 1. Twenty-three patients (53%) with LA thrombireceived oral anticoagulation therapy with phenprocou-mon before inclusion in the study. Nineteen patients(44%) had a history of embolisms. Nine of the patients(21%) had neurologic deficits at admission. All patientshad documented permanent atrial fibrillation, as shownby 12-lead surface electrocardiograms obtained duringfollow-up.

Measurements of left ventricular and atrial dimen-sions, left ventricular ejection fractions, and LA ap-pendage peak emptying velocities are given in Table2. At the index admission, the mean thrombi dimen-sions were 1.6 � 0.7 cm in length and 1.0 � 0.5 cmin width. All thrombi were located in the LA append-age. Twenty-four thrombi were mobile, 28 wereechodense, and 1 protruded into the left atrium. Spon-taneous echo contrast was present in all cases. Thir-teen patients had patent foramen ovale. Thirty-ninepatients had aortic plaques �4 mm. None of thepatients had mobile aortic atheroma.

During the follow-up of 12 months, 24 thrombi

(56%) disappeared: 16% at 1 month,42% at 3 months, 49% at 6 months,and 56% at 12 months (Figure 1).Thrombus size in patients withoutthrombus disappearance decreasedfrom 1.9 � 0.6 cm in length and 1.3� 0.4 cm in width to 1.4 � 0.6 cm inlength and 0.8 � 0.5 cm in width.Patients with persistent thrombi hadless frequent echodense thrombi af-ter the 12-month follow-up period(17 [89%] at index admission com-pared with 12 [63%] at the end of theobservation period).

Nine patients had old focal diffu-sion abnormalities at the index ad-mission. During the 12-month fol-low-up, 16% of the patients (7 of 43)manifested acute cerebral diffusionabnormalities in a pattern consistentwith embolic lesions. The size of theembolic lesions was �5 mm in 5lesions, 5 to 10 mm in 1 lesion, and�10 mm in 1 lesion. The affectedvascular territories were superficialmiddle cerebral arteries (n � 5) anddeep middle cerebral arteries (n �2). No diffusion abnormalities inborder zone areas or diffuse diffu-sion abnormalities were noted. Three

of 43 patients (7%) had new MRI findings at the1-month follow-up, 5 (12%) at the 3-month follow-up,and 7 (16%) at the 6-month follow-up (Figure 2).Patients with and without anticoagulation before studyenrollment did not differ with regard to events duringfollow-up.

Six patients had clinically apparent neurologic def-icits and cerebral infarctions as documented by cranialMRI. One patient had clinically silent cerebral embo-lism as documented by diffusion defects. In the latterpatient, follow-up conventional MRI was performedafter 3 months. The patient developed a focal signalhyperattenuation on the T2-weighted and fluid-atten-uated inversion recovery imaging in the region corre-sponding to the original index lesion, indicating in-farcted brain tissue.

Eight patients had carotid stenosis of �50%. Six ofthem had thrombus disappearance during follow-up.One patient had a cerebral lesion during the observa-tion period.

Twenty three patients (53%) were anticoagulatedeffectively at index admission. Fifteen patients witheffective anticoagulation at the admission had thrombiresolution, and 1 patient had a cerebral embolismduring follow-up. During the observation period, theaverage INR was 2.2 � 0.4. Patients with and withouteffective oral anticoagulation therapy did not differ inthe incidence of embolism (p � 0.24). The mean INRwas 2.3 � 0.4 before the occurrence of embolic eventsand 2.2 � 0.3 at the time of events.

Clinical risk factors did not differ between patientswith and without thrombus disappearance. Patients with

TABLE 3 Patients With and Without Thrombus Resolution

VariablePatients With

Thrombus ResolutionPatients Without

Thrombus Resolution

LA volume (cm3) 83 � 27* 116 � 55*Left ventricular end-diastolic volume (cm3) 163 � 59 149 � 68Left ventricular ejection fraction (%) 54 � 12 47 � 21Spontaneous echo contrast (grade) 3.1 � 0.6 2.9 � 0.5LA appendage peak emptying velocity (m/s) 0.24 � 0.08 0.26 � 0.08Thrombus length (cm) 1.5 � 0.8† 1.9 � 0.6†

Thrombus width (cm) 0.8 � 0.5† 1.3 � 0.4†

Echodense thrombus 11 (46%) 17 (89%)Mobile thrombus 14 (58%) 10 (53%)

*p �0.05; †thrombus size (length � width) p �0.05.

TABLE 4 Patients With and Without Embolism

VariablePatients With

EmbolismPatients Without

Embolism

LA volume (cm3) 91 � 49 100 � 45Left ventricular end-diastolic volume (cm3) 183 � 24 152 � 67Left ventricular ejection fraction (%) 48 � 21 52 � 16Spontaneous echo contrast (grade) 3.0 � 0.6 3.0 � 0.6Left atrial appendage peak emptying velocity (m/s) 0.33 � 0.08* 0.23 � 0.07*Thrombus length (cm) 2.1 � 0.7 1.5 � 0.7Thrombus width (cm) 1.2 � 0.6 1.0 � 0.5Echodense thrombus 5 (71%) 21 (58%)Mobile thrombus 4 (57%) 20 (56%)

*p �0.01.

BRIEF REPORTS 803

and without resolution did not differ in left ventriculardimensions (p � 0.48), left ventricular ejection fractions(p � 0.17), thrombus mobility (p � 0.71), patent fora-men ovale (p � 0.45), and spontaneous echo contrast (p� 0.37) (Table 3). However, patients with thrombusdisappearance during the observation period had smallerthrombi (1.5 � 0.8 cm in length and 0.8 � 0.5 cm inwidth vs 1.9 � 0.6 cm in length and 1.3 � 0.4 cm inwidth, 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 significantlygreater peak emptying velocities of the LA appendage(31 � 8 vs 23 � 7 cm/s, p �0.01) and more commonlyhad a history of thromboembolic events (5 [71%] vs 9[25%], p � 0.02). Patients with effective anticoagulationat the index admission had significantly less frequentembolic events than patients who began anticoagulationat 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 withmodern MRI techniques in patients with LA thrombiduring a 12-month follow-up period. Recent studieshave shown that diffusion-weighted cranial MRI mayserve as a useful surrogate end point for ischemicstroke.8–11 Cranial MRI examinations are suited toobjectively and quantitatively monitor thromboembo-lism in patients with atrial thrombi. Continued effec-tive anticoagulation does not prevent thromboembolicevents in patients with permanent AF and prevalentLA thrombi. In our study, embolism occurred even inpatients with effective anticoagulation (16%). Patientswith persistent thrombi should be observed closely.

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