A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) and cancer share elements of pathophysiology. This provides an opportunity for the cross-development of anticancer agents that can be used in improving PAH care. The adaptation of new drugs across these disease populations warrants a structured approach. This study was a 16-week, phase Ib, single-center, open-label trial of the multikinase/angiogenesis inhibitor sorafenib. In order to assess the safety of sorafenib in PAH, patients with advanced but stable disease on parenteral prostanoids (with or without oral sildenafil) were initiated on treatment at the lowest active dosage administered to cancer patients: 200 mg daily. Patients underwent weekly clinical evaluations and monthly functional testing and dose escalations to a final dosage of 400 mg twice daily. Among 12 patients (10 of them women), sorafenib was well tolerated at 200 mg twice daily. The most common adverse events were moderate skin reactions on the hands and feet and alopecia. Our conclusion was therefore that this is a tolerable dosing regimen for testing the therapeutic activity of sorafenib in PAH patients.

Evaluation of alterations on mitral annulus velocities, strain, and strain rates due to abrupt changes in preload elicited by parabolic flight.

We tested the hypothesis that in normal subjects, cardiac tissue velocities, strain, and strain rates (SR), measured by Doppler tissue echocardiography (DTE), are preload dependent. To accomplish it, immediately preceding image acquisition, reversible, repeatable, acute nonpharmacological changes in preload were induced by parabolic flight. DTE has been proposed as a new approach to assess left ventricular regional myocardial function by computing tissue velocities, strain, and SR. However, preload dependence of these parameters in normal subjects still remains controversial. DTE images (Philips) were obtained in 10 normal subjects in standing upright position at normogravity (1 Gz), hypergravity (1.8 Gz), and microgravity (0 Gz) with and without -50 mmHg lower body negative pressure (LBNP). Myocardial velocity curves in the basal interventricular septum were reconstituted offline from DTE images, from which peak systolic (S'), early (E') and late (A') diastolic velocities, SR, and peak systolic strain (PSepsilon) were measured and averaged over four beats. At 1.8 Gz (reduced venous return), S', E', and A' decreased by 21%, 21%, and 26%, respectively, compared with 1-Gz values, while at 0 Gz (augmented venous return), E', A', and PSepsilon increased by 57%, 53%, and 49%, respectively. LBNP reduced E' and PSepsilon. In conclusion, our results were in agreement with those obtained in animal models, in which preload was changed in a controlled, acute, and reversible manner, and image acquisition was performed immediately following preload modifications. The hypothesis of preload dependence was confirmed for S', E', A', and PSepsilon, while SR appeared to be preload independent, probably reflecting intrinsic myocardial properties.

Objective evaluation of changes in left ventricular and atrial volumes during parabolic flight using real-time three-dimensional echocardiography.

We tested the feasibility of real-time three-dimensional (3D) echocardiographic (RT3DE) imaging to measure left heart volumes at different gravity during parabolic flight and studied the effects of lower body negative pressure (LBNP) as a countermeasure. Weightlessness-related changes in cardiac function have been previously studied during spaceflights using both 2D and 3D echocardiography. Several technical factors, such as inability to provide real-time analysis and the need for laborious endocardial definition, have limited its usefulness. RT3DE imaging overcomes these limitations by acquiring real-time pyramidal data sets encompassing the entire ventricle. RT3DE data sets were obtained (Philips 7500, X3) during breath hold in 16 unmedicated normal subjects in upright standing position at different gravity phases during parabolic flight (normogravity, 1 Gz; hypergravity, 1.8 Gz; microgravity, 0 Gz), with LBNP applied (-50 mmHg) at 0 Gz in selected parabolas. RT3DE imaging during parabolic flight was feasible in 14 of 16 subjects. Data were analyzed (Tomtec) to quantify left ventricular (LV) and atrial (LA) volumes at end diastole and end systole, which significantly decreased at 1.8 Gz and increased at 0 Gz. While ejection fraction did not change with gravity, stroke volume was reduced by 16% at 1.8 Gz and increased by 20% at 0 Gz, but it was not significantly different from 1 Gz values with LBNP. RT3DE during parabolic flight is feasible and provides the basis for accurate quantification of LV and LA volume changes with gravity. As LBNP counteracted the increase of LV and LA volumes caused by changes in venous return, it may be effectively used for preventing cardiac dilatation during 0 Gz.

Improved quantification of left ventricular mass based on endocardial and epicardial surface detection with real time three dimensional echocardiography.

OBJECTIVE: To develop a technique for volumetric analysis of real time three dimensional echocardiography (RT3DE) data aimed at quantifying left ventricular (LV) mass and to validate the technique against magnetic resonance (MR) assumed as the reference standard. DESIGN: RT3DE, which has recently become widely available, provides dynamic pyramidal data structures that encompass the entire heart and allows four dimensional assessment of cardiac anatomy and function. However, analysis techniques for the quantification of LV mass from RT3DE data are fundamentally two dimensional, rely on geometric modelling, and do not fully exploit the volumetric information contained in RT3DE datasets. Twenty one patients underwent two dimensional echocardiography (2DE), RT3DE, and cardiac MR. LV mass was measured from 2DE and MR images by conventional techniques. RT3DE data were analysed to semiautomatically detect endocardial and epicardial LV surfaces by the level set approach. From the detected surfaces, LV mass was computed directly in the three dimensional space as voxel counts. RESULTS: RT3DE measurement was feasible in 19 of 21 patients and resulted in higher correlation with MR (r = 0.96) than did 2DE (r = 0.79). RT3DE measurements also had a significantly smaller bias (-2.1 g) and tighter limits of agreement (2SD = +/-23 g) with MR than did the 2DE values (bias (2SD) -34.9 (50) g). Additionally, interobserver variability of RT3DE (12.5%) was significantly lower than that of 2DE (24.1%). CONCLUSIONS: Direct three dimensional model independent LV mass measurement from RT3DE images is feasible in the clinical setting and provides fast and accurate assessment of LV mass, superior to the two dimensional analysis techniques.

Feasibility of real-time 3D echocardiography in weightlessness during parabolic flight.

Aim of the study was to test the feasibility of transthoracic real-time 3D (Philips) echocardiography (RT3D) during parabolic flight, to allow direct measurement of heart chambers volumes modifications during the parabola. One RT3D dataset corresponding to one cardiac cycle was acquired at each gravity phase (1 Gz, 1.8 Gz, 0 Gz, 1.8 Gz) during breath-hold in 8 unmedicated normal subjects (41 +/- 8 years old) in standing upright position. Preliminary results, obtained by semi-automatically tracing left ventricular (LV) and left atrial (LA) endocardial contours in multiple views (Tomtec), showed a significant (p<0.05) reduction, compared to 1 Gz, of LV and LA volumes with 1.8 Gz, and a significant increase with 0 Gz. Further analysis will focus on the right heart.

Power Doppler imaging as a basis for automated endocardial border detection during left ventricular contrast enhancement.

Echocardiographic evaluation of left ventricular (LV) systolic function relies on endocardial visualization, which can be improved when necessary using contrast enhancement. However, there is no method to automatically detect the endocardial boundary from contrast-enhanced images. We hypothesized that this could be achieved using harmonic power Doppler imaging. Twenty-two patients were studied in two protocols: (1) 11 patients with poorly visualized endocardium (> 3 contiguous segments not visualized) and (2) 11 consecutive patients referred for dobutamine stress echocardiography who were studied at rest and at peak dobutamine infusion. Patients were imaged in the apical four-chamber view using harmonic power Doppler mode (HP SONOS 5500) during LV contrast enhancement (Optison or Definity DMP115). Digital images were analyzed using custom software designed to automatically extract the endocardial boundary from power Doppler color overlays. LV cavity area was automatically measured frame-by-frame throughout the cardiac cycle, and fractional area change calculated and compared with those obtained by manually tracing the endocardial boundary in end-systolic and end-diastolic gray scale images. Successful border detection and tracking throughout the cardiac cycle was possible in 9 of 11 patients with poor endocardial definition and in 10 of 11 unselected patients undergoing dobutamine stress testing. Fractional area change obtained from power Doppler images correlated well with manually traced area changes (r = 0.82 and r = 0.97, in protocols 1 and 2, respectively). Harmonic power Doppler imaging with contrast may provide a simple method for semi-automated border detection and thus facilitate the objective evaluation of LV function both at rest and under conditions of stress testing. This methodology may prove to be particularly useful in patients with poorly visualized endocardium.

Three-dimensional echocardiography in adult patients: comparison between transthoracic and transesophageal reconstructions.

BACKGROUND: Three-dimensional (3D) echocardiography is a relatively new technique typically implemented with transesophageal imaging with multiplane transducers. OBJECTIVES: The goals of this study were (1) to test the feasibility of 3D reconstruction with a new transthoracic multiplane transducer in adult subjects with excellent quality of 2-dimensional images and (2) to compare these reconstructions with those obtained in the same patients with the transesophageal approach. METHODS: Transthoracic multiplane image acquisition was performed in 37 patients who were selected on the basis of the quality of their 2-dimensional images. In addition, transesophageal acquisition was also performed in 19 of 37 patients. Three-dimensional reconstruction of mitral and aortic valves was performed. Three-dimensional images were reviewed, and the visualization of various anatomic features was graded. RESULTS: The reconstruction of 25 mitral valves and 16 aortic valves, normal and pathologic, was feasible and resulted in visualization of anatomic detail. Score indexes of all valvular characteristics studied were not significantly different when transthoracic and transesophageal reconstructions were compared. CONCLUSIONS: Transthoracic 3D echocardiography with a multiplane transducer in adult patients with good acoustic windows is feasible. This technique will allow easy noninvasive serial assessment of valvular pathophysiologic characteristics.

Identification of cardiac masses and abnormal blood flow patterns with harmonic power Doppler contrast echocardiography.

Power Doppler is an ultrasound technique that color-encodes the change in amplitude of the ultrasound signal, which reflects changes in the position of scatterers between ultrasound pulses. Power Doppler can be used with echocardiographic contrast agents in a harmonic imaging mode to opacify a cardiac chamber. The opacification of a cardiac chamber can aid in visualizing the silhouette of intracardiac masses and displaying blood flow patterns. Four cases are presented that demonstrate the use of harmonic power Doppler to aid in the identification of a left ventricular apical thrombus, a left atrial thrombus, and a left ventricular pseudoaneurysm.

New insights and observations in three-dimensional echocardiographic visualization of ventricular septal defects: experimental and clinical studies.

BACKGROUND: The positions, sizes, and shapes of ventricular septal defects (VSDs) can be difficult to assess by 2-dimensional echocardiography (2DE). Volume-rendered 3-dimensional echocardiography (3DE) can provide unique views of VSDs from the left ventricular (LV) side, allowing complete assessment of their circumference and spatial orientations to other anatomic structures. METHODS AND RESULTS: Seventeen experimentally created defects of various locations, sizes, and shapes were imaged and reconstructed in 9 explanted porcine hearts. From an en face projection, major and minor axis diameters of the defects were measured, and these data were compared with direct anatomic measurements. Optimal reconstructions of the VSDs were obtained in all heart specimens, accurately depicting their positions and shapes. The correlations between 3DE and anatomy for the VSD major and minor axis diameters were y=1.0x+0.3 (r=0.88, P<0.001) and y=1.0x-1.4 (r =0.89, P<0.001), respectively. Good agreement between the 2 methods was demonstrated for all measurements. Our experience from the in vitro model was then applied to patient studies. Optimal LV en face reconstructions were obtained in 45 of 51 patients, permitting detailed assessment of the positions, sizes, and shapes of the VSDs. In the 25 patients with comparative surgical measurements, the correlations between 3DE and surgery for the VSD major and minor axis diameters were y =0. 81x+2.1 (r=0.92, P<0.001) and y=0.73x+2.0 (r=0.91, P<0.001), respectively. Good agreement was demonstrated between measurements made by 3DE and those obtained at surgery. CONCLUSIONS: 3DE provides excellent visualization of various types of VSDs. From an LV en face projection, the positions, sizes, and shapes of VSDs can be accurately determined. Such precise imaging will be beneficial for surgical and catheter-based closure of difficult perimembranous and singular or multiple muscular VSDs.

Two- and three-dimensional transesophageal echocardiography in patient selection and assessment of atrial septal defect closure by the new DAS-Angel Wings device: initial clinical experience.

BACKGROUND: Transcatheter closure of atrial septal defects (ASDs) has been feasible and successful. Two-dimensional echocardiography (2DE) was applied to patients before selection and during device deployment. Three-dimensional echocardiography (3DE) can provide unique anatomic perspectives that might aid in improving device closure of ASDs. METHODS AND RESULTS: Twenty-two consecutive patients were enrolled in an initial protocol for ASD device closure by the new DAS-Angel Wings occluder device. On the basis of transesophageal (TEE) 2DE and 3DE, 13 patients were considered eligible for device closure (9 secundum ASDs and 4 with patent foramen ovale associated with a cerebral vascular accident). Maximal ASD diameter and surrounding rim tissues were compared by TEE 2DE and 3DE and with balloon sizing measurements at catheterization. ASD size measured by TEE 2DE and 3DE correlated well (y = 1.0x + 0.049, r = .95), with good limits of agreement. However, balloon-stretched diameter measurements were systematically larger than echocardiographic measurements. Rim tissue measurements correlated well; however, TEE 3DE could demonstrate the entire shape and perimeter of the defect. Two-dimensional imaging provided reliable information during device deployment and for closure of small ASDs. However, 3DE was superior for imaging the device, especially when abnormally placed. CONCLUSIONS: Three-dimensional imaging provides unique images and projections that were essential for understanding the spatial relationship of the device to the atrial septum. Three-dimensional echocardiography significantly enhanced our understanding of two-dimensional images and provided an imaging conceptualization that should aid in future development of device closures.

Three-dimensional echocardiographic evaluation of aortic disorders with rotational multiplanar imaging: experimental and clinical studies.

Transesophageal echocardiography has become a highly valuable method to assess aortic disorders. With this method, however, aortic disease has been visualized only in two-dimensional views. Advances in computer technology have introduced three-dimensional (3D) echocardiography as a developing modality in cardiac imaging. Previous efforts to obtain 3D reconstructions of the aorta, by various techniques, had limited clinical applicability. In this study we attempted to explore the feasibility and potential of 3D reconstructions of the aorta employing a widely used multiplane transesophageal imaging technique in an experimental setting and in patients. In the in vitro study, we created 35 lesions in 28 pig aortic trees (15 aortic dissections, five saccular aneurysms, five coarctations, five atheromas, and five clots within dissections). Suspending these specimens in a water bath, sequential two-dimensional images were acquired over a 180-degree rotation with a commercially available multiplane transesophageal probe and ultrasound system with a 3D software package. Data processing (digital reformation, interpolation, and segmentation) and 3D display were accomplished on an off-line computer system. 3D reconstructions were achieved and displayed in wire-frame, surface-rendered, and volume-rendered images. These 3D reconstructions corresponded well with the actual anatomic specimens in delineating the various pathologic findings. In patient studies, we collected a total of 36 studies in both adults and children with a mean age of 44.5 years (range 1 month to 82 years). In addition to normal aortas (n = 13), the spectrum of abnormalities studied included six atheromatous lesions, four aortic dissections, 10 coarctations, one aneurysm with a thrombus, and one dilated aortic root. We were able to accomplish volume-rendered 3D images depicting the aortic lesions in their true form that could be viewed in many different perspectives in all patients. We conclude that 3D echocardiography is able to display the aorta and aortic disease in a realistic manner. Although this modality still has limitations, further improvements in computer and ultrasound technology would strengthen 3D echocardiography as a clinically viable diagnostic tool, in the evaluation of aortic disorders.

Volume-rendered, three-dimensional echocardiographic determination of the size, shape, and position of atrial septal defects: validation in an in vitro model.

Accurate evaluation of atrial septal defect (ASD) size and shape is very important for the selection of patients for transcatheter occlusion. The ability of volume-rendered, three-dimensional echocardiography (3DE) in displaying ASDs in a dynamic mode has been demonstrated; however, its accuracy in sizing ASDs is unknown. To assess this, we performed 3DE of 10 explanted pig hearts in which ASDs of various locations, sizes, and shapes had been experimentally created. From en face 3DE views of the atrial septum containing the defects, major and minor diameters of the defect were measured by a blinded observer, and these data were compared to direct anatomic measurements. The correlations between 3DE and anatomy for the major and minor ASD diameters were y = 0.83x + 3.4 (r = 0.97, p < 0.0001) and y = 0.92x + 1.3 (r = 0.92, p < 0.0001) respectively. The correlation between the measures for major and minor axis ratio was y = 1.06 x - 0.052, r = 0.91, p < 0.0002. Good agreement between both methods of measurements was demonstrated for all measurements. In addition, 3DE portrayed the location and shape of the defects accurately. Thus 3DE provides excellent visualization of ASD and is able to accurately define the size of the defects. These qualitative and quantitative capabilities enhance the clinical potential of this technique in the appraisal of ASDs for decisions regarding application of closure devices.

Dynamic three-dimensional echocardiographic assessment of intracardiac blood flow jets.

Transthoracic dynamic 3-dimensional reconstruction of the heart with tissue depiction has been proved to be feasible when using various methods of data acquisition. The same method can theoretically be applied to color Doppler flows to generate dynamic 3-dimensional images of intracardiac blood flow jets. To explore the feasibility of this approach, we studied 41 patients with various valvular disorders or intracardiac shunts. We acquired sequential 2-dimensional images along with color Doppler information using rotational scanning from a transthoracic or a subcostal window. Images were digitized and processed for 3-dimensional reconstruction using dedicated software. After adequate segmentation, the flow jets were displayed in 3 dimensions in a gray scale format. With use of this approach, 3-dimensional reconstruction of color Doppler flows was possible in all but 1 patient. Still frames allowed immediate appreciation of the shape of the jets, their location in the cardiac chambers, and their size related to that cavity. Dynamic display was even more striking by showing the flow in real time. Dynamic 3-dimensional images enabled visualization of flow jets in projections not available in conventional color flow Doppler, looking directly at the views of shunt and regurgitant flows, and also permitted 3-dimensional delineation of flow convergence zones. We conclude that dynamic visualization of various intracardiac flows in 3 dimensions using transthoracic echocardiography is possible. It provides a better understanding of the shape and size of the jets, and can potentially aid in flow quantification by displaying the actual shape of flow convergence regions.

Volumetric multiplexed transmission holography of the heart with echocardiographic data.

Three-dimensional imaging enhances delineation of cardiac anatomy and function. Currently, three-dimensional echocardiography involves complex rendering techniques to imply depth in a given image. Also, display of the final images on a video monitor neutralizes the volume information of the object. A hologram is a true, three-dimensional replica of the original object and does not entail complex data processing. Holography has not been used previously in cardiovascular imaging. In this experiment, 11 excised mammalian whole hearts and five isolated left ventricles were imaged in a water bath. Parallel, tomographic, echocardiographic images comprised the data source from which holograms were obtained by the technique of multiplexed holography. Holograms were mounted on a holographic film and viewed in a special viewing box. High-quality holograms were obtained from every data set. Excellent gray-scale discrimination allowed crisp visualization of cardiac structures and simulated diseases. Electronic sectioning and various projections optimized viewing of the three-dimensional anatomy in surgical orientations. Thus holograms can be produced from tomographic cardiac ultrasound data and could open a new avenue in three-dimensional echocardiography.

Delineation of site, relative size and dynamic geometry of atrial septal defects by real-time three-dimensional echocardiography.

OBJECTIVES: This study attempted to determine the site, relative size and dynamic geometry of atrial septal defects using dynamic three-dimensional echocardiography. BACKGROUND: Recent studies have demonstrated the feasibility of dynamic three-dimensional echocardiography. Images are acquired from computerized reconstruction of sequential, tomographic ultrasound "slices" of the heart. Ultrasound images can be obtained by linear progression of a transducer within a transesophageal imaging probe. In small infants and children the large transducer size has not allowed transesophageal placement, and the probe has been placed on the thorax or in the subcostal position. Other scanning devices, housed in plastic containers, acquire images in a rotational format and can also be placed in a transthoracic or subcostal position. METHODS: Specially designed transesophageal probes and a dedicated computer unit were used for two-dimensional image retrieval and reconstruction of three-dimensional images. Sixteen patients with atrial septal defects were studied (median age 18 months, range 1 day to 18 years). In one patient, images were obtained by transesophageal probe placement; in the other 15 patients, the probe was placed in the transthoracic or subcostal position. RESULTS: A dynamic three-dimensional echocardiogram of the atrial septal defect could be obtained in 13 of the 16 patients. The distinguishing features of the atrial septal defects and their spatial orientation could be visualized in unique three-dimensional views. CONCLUSIONS: Dynamic three-dimensional imaging could be applied to the specific evaluation of atrial septal defects. Unique views of the heart allowed for spatial comprehension of the defects, rendering potentially important clinical information.

Transthoracic real-time three-dimensional echocardiography using a fan-like scanning approach for data acquisition: methods, strengths, problems, and initial clinical experience.

Three-dimensional echocardiography is an emerging clinical method to assess cardiovascular disorders. The feasibility of using a linear mode scanning (parallel slicing) for transthoracic data acquisition has been demonstrated. In this study, we evaluated the feasibility of real-time transthoracic three-dimensional imaging of the heart using a fan-like scanning mode of echocardiographic data acquisition. We used a computer-driven motor to sequentially angulate transthoracic transducers over a fan-like arc up to 90 degrees. With careful ECG and respiratory gating, we acquired basic two-dimensional data set via parasternal and subcostal windows and performed dynamic three-dimensional reconstructions. The problems encountered included the need to repeat data acquisition sequences because of transducer movement or inappropriate gain and gray scale settings. From 15 scanning sequences in four patients, we were able to use ten sets of data. These yielded good quality three-dimensional studies projecting normal valves, a stenotic mitral valve, and an atrial septal defect, in a number of novel views. The valves could be visualized from above and from below as well as in other orientations, and the detailed anatomy appraised. Spatial relationships of the atrial septal defect with inferior and superior vena cava, coronary sinus, or tricuspid annulus could be uniquely displayed through views from the right side of the heart. This technique provided adequate new imaging planes not available from two-dimensional echocardiography. This experience demonstrates for the first time that transthoracic three-dimensional echocardiography using a fan-like scanning mode of data acquisition is feasible, and that it provides adequate visualization of intracardiac structures in unique projections.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic three-dimensional echocardiography: methods and clinical potential.

In this article, we will attempt to review basic requirements for three-dimensional reconstruction, methods of cavity reconstruction, approaches to gray scale tissue-depiction displays, and current clinical experience, and also present some directions for future development.