Study Population

This study was part of a 6-year (December 2006 to December 2012) research protocol approved by the National Institutes of Health and the institutional review board for the study of cardiovascular and cerebrovascular disease in patients with SLE. The results of that study in 102 subjects (76 patients with SLE and 26 healthy controls) using 2D TEE have been published. All participants provided informed consent.

From February 2010 (when 3D TEE became available at our institution) to December 2012 (the end of study funding and authorized enrollment), 29 patients with SLE (27 women; mean age, 34 ± 12 years; range, 18–55 years) prospectively underwent clinical and laboratory evaluations, brain magnetic resonance imaging (MRI), neurocognitive assessment, and 40 paired 3D and 2D transesophageal echocardiography studies (11 studies were repeated to reassess cardiac and brain disease after anti-inflammatory and/or antithrombotic therapy after patients’ first or during recurrent neurologic events). The 40 paired transesophageal echocardiographic studies constitute the basis for this study.

Patients with suspected heart and brain disease unrelated to SLE, including any febrile illness and infective endocarditis, were excluded from participation in the study.

Clinical, laboratory, brain MRI, and initial and repeat paired transesophageal echocardiographic studies in patients were intermixed in a blinded manner with paired studies from healthy controls and were deidentified, coded, and independently interpreted by experienced observers unaware of patients’ clinical and imaging data.

Clinical, Brain MRI, and Laboratory Evaluations

On enrollment, patients were prospectively assessed for the presence of (1) acute focal and nonfocal neurologic syndromes of stroke, transient ischemic attack (TIA), confusional state, cognitive dysfunction, or seizures ; (2) focal brain injury on MRI, defined as old or recent cerebral infarcts or periventricular or deep white matter abnormalities ; and (3) global neurocognitive dysfunction, defined as ≥1.5 SDs below the mean of healthy controls. Patients were also characterized with regard to SLE duration, activity, damage, standard serology, autoantibodies including antiphospholipid antibodies, and anti-inflammatory and anti-thrombotic therapy ( Table 1 ).

Transesophageal Echocardiography

Participants underwent concurrent, complete 3D and 2D TEE with Philips iE33 systems (Philips Medical Systems, Andover, MA) using a 7-MHz 3D matrix-array transducer. Images were digitally acquired for offline reconstruction (for 3D transesophageal echocardiographic images) and interpretation.

Using 2D TEE and from the basal to the midesophageal level, the mitral and aortic valves were imaged in multiple planes at a depth of 4 to 8 cm with a narrow sector scan to improve image resolution.

Using 3D TEE and from the basal to the midesophageal level, 0° to 120° views of the mitral valve and 30° to 60° short-axis and 110° to 130° long-axis views of the aortic valve were acquired. To achieve the highest spatial and temporal resolution, electrocardiographically triggered multiple-beat (four beats) high-density full-volume images with the narrowest possible sector scan were obtained during breath holding (expiration). Three-dimensional transesophageal echocardiographic full-volume data sets were acquired with gain and compression settings of ≥50 units and then cropped and multiplane transected to obtain en face atrial and left ventricular views of the mitral valve and aortic root and left ventricular outflow tract views of the aortic valve.

Two-dimensional and 3D transesophageal echocardiographic images were acquired during the same examination, and both types of images were collected by the same examiner using the same probe.

Also, 2D transesophageal echocardiographic images were acquired in a systematic order using single-plane or, infrequently, x-plane tomographic planes. In addition, volumetric images were obtained in a systematic manner independently of identifying or not valve pathology on single tomographic planes. Furthermore, for best quality matching of 2D and 3D transesophageal echocardiographic images, 3D transesophageal echocardiographic volumetric images were obtained immediately after the best corresponding 2D images.

To reduce interpretation bias toward 3D TEE, the following steps were taken: (1) No live 3D images were obtained or recorded during the performance of TEE. (2) All deidentified 2D transesophageal echocardiographic studies were first interpreted by one experienced observer (C.A.R.). In 22 randomly selected 2D transesophageal echocardiography studies, interobserver agreement (C.A.R. and G.C.) for detection of vegetations of the mitral, aortic, and either valve were 82% (κ = 0.61), 96% (κ = 0.91), and 91% (κ = 0.80), respectively. (3) At a later time and to preserve the highest image resolution, 3D transesophageal echocardiographic studies of the mitral and aortic valves were identified by analyzing the volumetric data sets using multiplanar reconstruction in the ultrasound imaging systems by an experienced observer (D.M.) who was not an interpreter of transesophageal echocardiographic studies. These images were usually added at the end of the study. (4) Finally, 3D transesophageal echocardiographic studies were independently interpreted by two experienced observers (C.A.R. and K.T.) unaware of earlier 2D transesophageal echocardiographic interpretations. For all 3D transesophageal echocardiographic studies, interobserver agreement (C.A.R. and K.T.) for the detection of vegetations of the mitral, aortic, and either valve were 89% (κ = 0.78), 97% (κ = 0.92), and 96% (κ = 0.92), respectively.

Criteria for 3D and 2D TEE Interpretation

Libman-Sacks vegetations by either technique were defined as abnormal localized, protruding, and sessile echodensities >3 mm in diameter with well-defined borders either as part of or adjacent to valve leaflets, annulus, subvalvular apparatus, or endocardial surfaces. The cutoff of >3 mm in diameter was adopted to prevent misinterpretation of Lambl’s excrescences as vegetations. Lambl’s excrescences are thin (usually ≤2 mm in width, rarely up to 3 mm), elongated (usually >5 mm in length), independently hypermobile, and homogeneously echoreflectant structures located at the coaptation point and atrial side of the mitral valve and ventricular side of the aortic valve. By both techniques, location of the mitral valve vegetations with regard to anterior or posterior leaflets; basal, middle, or distal portions of the leaflets; corresponding scallops (anterolateral [A1, P1], middle [A2, P2], or posteromedial [A3, P3]); and atrial or ventricular side of the leaflets was determined. Location of the aortic valve vegetations with regard to left, right, or noncoronary cusps; tip, body, or margin of the cusps; and ventricular or aortic side of the cusps was also determined.

Using multiplane 2D TEE, the maximum diameter and area of vegetations were measured. With 3D TEE, the maximum diameter and area of vegetations were measured from the anteroposterior, superoinferior, and mediolateral dimensions. These 3D transesophageal echocardiographic measurements were performed offline using QLAB (Philips Medical Systems) and multiplanar reconstruction mode. For both techniques and using electronic calipers, three measurements during three different cardiac cycles were performed, and the maximum diameters and areas were analyzed.

The presence and severity of associated mitral valve anterolateral or posteromedial commissural fusion was assessed from the atrial view and defined as mild, moderate, or severe when involving less than or equal to one-third, up to two-thirds, or the entire corresponding commissural scallops, respectively. Aortic valve commissural fusion was assessed from the aortic root view and defined as mild, moderate, or severe when the corresponding cusps were fused less than or equal to one-third, up to two-thirds, or extended to the cusps’ central coaptation point, respectively.

Finally, the detection of valve vegetations by 3D and 2D TEE in relation to acute clinical neurologic syndromes, focal brain injury on MRI, neurocognitive dysfunction, or the combination of these three outcomes was determined.

Statistical Analysis

Descriptive statistics are presented as frequency (percentage) and as mean ± SD. Paired comparison of the number of 3D versus 2D transesophageal echocardiographic studies with vegetations and the frequency of vegetations by either technique in relation to cerebrovascular disease were performed using the McNemar test. The individual mean counts of vegetations per study are reported as Poisson means. These mean counts with regard to locations (distal vs middle or proximal leaflet and middle [A2 or P2] vs anterolateral or posteromedial [A1, P1 or A3, P3] scallops for the mitral valve leaflets and left coronary cusp, noncoronary cusp, or right coronary cusp and cusp tip, body, or margin for the aortic valve cusps) as repeated factors were done by Poisson regression (PROC GENMOD in SAS; SAS Institute, Inc, Cary, NC). The comparisons of diameters and areas of vegetations between 3D and 2D TEE were done using paired t tests. Two tailed P values ≤ .05 were considered to indicate statistical significance. All statistical analyses were performed using SAS version 9.3.

Clinical and Laboratory Evaluations

Among the 40 patients with SLE who underwent TEE, a total of 34 (85%) had one or more manifestations of cerebrovascular involvement: 23 (58%) patients had acute neurologic syndromes, 25 (63%) had focal brain injuries on MRI, and 27 (68%) had neurocognitive dysfunction. As shown in Table 1 , patients with SLE were young, had a mean disease duration of 6.2 years, and had high levels of inflammatory markers; nearly 60% had positive antiphospholipid antibodies, the majority (55%) had been receiving prednisone for nearly 5 years, 41% were on nonsteroidal immunosuppressive therapy, and 38% were on antiplatelet or anticoagulant therapy.

Detection and Characterization of Libman-Sacks Vegetations by 3D and 2D TEE

As shown in Table 2 , the results of 3D TEE compared with 2D TEE were more often positive for mitral valve, aortic, and either valve vegetations ( P < .05 for all); 3D TEE detected a larger number of aortic valve vegetations and either valve vegetations (Poisson regression, P ≤ .001 for both), with a trend toward mitral valve vegetations ( P = .09); and 3D TEE determined larger diameter and area of mitral valve vegetations ( P < .05 for both) and larger maximum diameter of aortic valve vegetations ( P = .005).

Also, as shown in Table 3 , 3D TEE compared with 2D TEE improved the localization of vegetations. Three-dimensional TEE detected more vegetations on the anterior mitral leaflet, anterolateral (A1, P1) and posteromedial (A3, P3) mitral scallops, and the ventricular side or both ventricular and atrial sides (vegetations probably extending into both sides) of the leaflets ( P < .05 for all) ( Figures 1–3 , Videos 1A–1F, 2A–2D, 3A, and 3B ; available at www.onlinejase.com ). In addition, 3D TEE detected a larger number of vegetations on the anterior or posterior mitral leaflets with an oval, tubular or roll-like, coalescent, or clustered shape affecting two or three contiguous scallops ( P = .03) ( Figures 1–3 ). The locations of mitral valve vegetations on the ventricular side or on both sides of the leaflets and vegetations affecting two or more contiguous scallops were originally described by Libman and Sacks. Furthermore, 3D TEE detected more aortic valve vegetations on the noncoronary cusps, on the coronary cusps’ tips and margins, and on both the aortic and ventricular sides (vegetations extending into both sides) of the cusps ( P ≤ .02 for all) ( Figures 4 and 5 , Videos 4A, 4B, 5A, and 5B ; available at www.onlinejase.com ).

A 26-year-old woman with SLE with past stroke and acute transient ischemic attack. (A) This 2D TEE four-chamber view demonstrates small, irregularly shaped, sessile, and homogeneously hyperreflectant nodularities consistent with healed Libman-Sacks vegetations ( arrows ) on the left atrial (LA) side and distal portions of the anterior mitral leaflet (aml) and posterior mitral leaflet (pml) associated with mild leaflet thickening and severely decreased mobility of the pml (see Video 1A ). (B) This 3D TEE LA view of the mitral valve during systole demonstrates the additional findings of multiple, small to medium-size, protruding, sessile, predominantly oval shaped, and homogeneously echoreflectant nodularities ( arrows ) involving all scallops and mostly but not exclusively located at the tip of both leaflets (see Video 1B ). (C) This 3D TEE left ventricular (LV) view of the mitral valve during systole also demonstrates (1) multiple, small to medium-size, protruding, and homogeneously echoreflectant nodularities ( arrows ) located mainly at the tip of the anterior and posterior mitral leaflets and (2) three small to medium-size, oval and tubular shaped, sessile, and with brown discoloration vegetations located on the tip and commissural portion of P3, the tip of P2, and the tip of P1 scallops ( arrowheads ), suggestive of recently formed vegetations (see Video 1C ). (D) This 3D TEE LV view of the mitral valve during diastole demonstrates (1) multiple nodularities with homogeneous ( arrows ) and heterogeneous ( arrowheads ) echoreflectance along the tip of both mitral leaflets ( arrows ); (2) decreased mobility of both leaflets, of severe degree for the posterior leaflet with fixed P1 and P2 scallops; and (3) a mild degree of anterolateral commissural fusion ( horizontal arrow ) (see Video 1C-D ). (E) This 2D TEE two-chamber view demonstrates a large oval and homogeneously soft tissue echoreflectant mass suggestive of a recently formed vegetation ( arrow ) located at the junction of the posteromedial papillary muscle tip and chorda tendineae (see Video 1E ). (F) This 3D TEE LV view of the subvalvular mitral valve apparatus demonstrates a medium size chordal vegetation ( horizontal arrow ) in addition to multiple nodularities (probably healed vegetations) on the tip portion of both mitral leaflets (see Video 1F ). Associated moderate mitral regurgitation was demonstrated by color Doppler. (G) This photograph of the middle scallop of the pml demonstrates sessile, granular, protruding, grayish to brown discoloration, clustered, and coalescent Libman-Sacks vegetations ( arrows ) located on the coaptation point and predominantly on the atrial side, but also extending to the ventricular side of the leaflet. (H) This hematoxylin and eosin (H&E) histopathologic section at low magnification (2×) of the pml demonstrates diffuse thickening predominant of the leaflet tip with a well-adhered vegetation mainly on the atrial side, but also extending to the ventricular side ( arrows ). Note that the demarcation between the vegetation and leaflet is poorly defined. (I) This H&E histopathologic section of the Libman-Sacks vegetation at higher magnification (4×) demonstrated areas of fibrinoid necrosis ( black arrowhead ), focal hemorrhages ( white arrowhead ), few scattered acute inflammatory infiltrates, and interspersed fibrinous thrombi deposition ( pink color tissue ). Of note, the patient’s brain histopathology also confirmed multiple micro- and macroinfarcts in different stages and a thrombotic vasculopathy.

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