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Penetration of nanoscale therapeutic agents into the extracellular matrix (ECM) of a tumor is a limiting factor for the sufficient delivery of drugs in tumors. Ultrasound (US) in combination with microbubbles causing cavitation is reported to improve delivery of nanoparticles (NPs) and drugs to tumors. Acoustic radiation force (ARF) could also enhance the penetration of NPs in tumor ECM. In this work, a collagen gel was used as a model for tumor ECM to study the effects of ARF on the penetration of NPs as well as the deformation of collagen gels applying different US parameters (varying pressure and duty cycle). The collagen gel was characterized, and the diffusion of water and NPs was measured. The penetration of NPs into the gel was measured by confocal laser scanning microscopy and numerical simulations were performed to determine the ARF and to estimate the penetration distance and extent of deformation. ARF had no effect on the penetration of NPs into the collagen gels for the US parameters and gel used, whereas a substantial deformation was observed. The width of the deformation on the collagen gel surface corresponded to the US beam. Comparing ARF caused by attenuation within the gel and Langevin pressure caused by reflection at the gel-water surface, ARF was the prevalent mechanism for the gel deformation. The experimental and theoretical results were consistent both with respect to the NP penetration and the gel deformation.

Dual-frequency band probes are needed for ultrasound (US) reverberation suppression and are useful for image-guided US therapy. A challenge is to design transducer stacks that achieve high bandwidth and efficiency at both operating frequencies when the frequencies are widely separated with a frequency ratio ∼6:1-20:1. This paper studies the loading and backing conditions of transducers in such stacks. Three stack configurations are presented and analyzed using one-dimensional models. It is shown that a configuration with three layers of material separating the transducers is favorable, as it reduces high frequency ringing by ∼20 dB compared to other designs, and matches the low frequency (LF) transducer to the load at a lower frequency. In some cases, the LF load matching is governed by a simple mass-spring interaction in spite of having a complicated matching structure. The proposed design should yield improved performance of reverberation suppression algorithms. Its suitability for reduction of probe heating, also in single-band probes, should be investigated.

The mechanism involved in the ultrasoundenhanced intracellular delivery of fluorescein-isothiocyanate (FITC)-dextran (molecular weight 4 to 2000 kDa) and liposomes containing doxorubicin (Dox) was studied using HeLa cells and an ultrasound transducer at 300 kHz, varying the acoustic power. The cellular uptake and cell viability were measured using flow cytometry and confocal microscopy. The role of endocytosis was investigated by inhibiting clathrin- and caveolae-mediated endocytosis, as well as macropinocytosis. Microbubbles were found to be required during ultrasound treatment to obtain enhanced cellular uptake. The percentage of cells internalizing Dox and dextran increased with increasing mechanical index. Confocal images and flow cytometric analysis indicated that the liposomes were disrupted extracellularly and that released Dox was taken up by the cells. The percentage of cells internalizing dextran was independent of the molecular weight of dextrans, but the amount of the small 4-kDa dextran molecules internalized per cell was higher than for the other dextrans. The inhibition of endocytosis during ultrasound exposure resulted in a significant decrease in cellular uptake of dextrans. Therefore, the improved uptake of Dox and dextrans may be a result of both sonoporation and endocytosis.

SURF contrast imaging, as described previously in the literature, is a contrast agent detection technique achieved by processing of the received signals from transmitted dual frequency band pulse complexes with overlapping high-frequency (HF) and low-frequency (LF) pulses. The transmitted HF pulses are used for image reconstruction, whereas the transmitted LF pulses are used to manipulate the scattering properties of the contrast agent. As with harmonic contrast agent detection techniques, nonlinear wave propagation will, in most situations, also limit the specificity with the SURF contrast technique when transmitting overlapping HF and LF pulses. The present paper proposes an alternative SURF contrast imaging technique using transmit dual frequency band pulse complexes with non-overlapping HF and LF pulses. If the frequency of the LF manipulation pulse is close to the bubble resonance frequency, numerical simulations indicate a significant ring-down effect of the LF bubble radius response. Utilizing this bubble ring-down effect and transmitting the HF pulse just after the LF pulse, a contrast agent specificity approaching infinity accompanied by a contrast agent sensitivity only for contrast bubbles having resonance frequencies within a narrow frequency range may be obtained.

A method of acoustic imaging is discussed that potentially can improve the diagnostic capabilities of medical ultrasound. The method, given the name second order ultrasound field imaging, is achieved by the processing of the received signals from transmitted dual frequency band pulse complexes with at least partly overlapping high frequency (HF) and low frequency (LF) pulses. The transmitted HF pulses are used for image reconstruction whereas the transmitted LF pulses are used to manipulate the elastic properties of the medium observed by the HF imaging pulses. In the present paper, nonlinear propagation effects observed by a HF imaging pulse due to the presence of a LF manipulation pulse is discussed. When using dual frequency band transmit pulse complexes with a large separation in center frequency (e.g., 1:10), these nonlinear propagation effects are manifested as a nonlinear HF propagation delay and a HF pulse distortion different from conventional harmonic distortion. In addition, with different transmit foci for the HF and LF pulses, nonlinear aberration will occur.

A post-processing adjustment technique to enhance dual-frequency second-order ultrasound field (SURF) reverberation-noise suppression imaging in medical ultrasound is analyzed. Two variant methods are investigated through numerical simulations. They both solely involve post-processing of the propagated high-frequency (HF) imaging wave fields, which in real-time imaging corresponds to post-processing of the beamformed receive radio-frequency signals. Hence, the transmit pulse complexes are the same as for the previously published SURF reverberation-suppression imaging method. The adjustment technique is tested on simulated data from propagation of SURF pulse complexes consisting of a 3.5-MHz HF imaging pulse added to a 0.5-MHz low-frequency soundspeed manipulation pulse. Imaging transmit beams are constructed with and without adjustment. The post-processing involves filtering, e.g., by a time-shift, to equalize the two SURF HF pulses at a chosen depth. This depth is typically chosen to coincide with the depth where the first scattering or reflection occurs for the reverberation noise one intends to suppress. The beams realized with post-processing show energy decrease at the chosen depth, especially for shallow depths where, in a medical imaging situation, a body-wall is often located. This indicates that the post-processing may further enhance the reverberation- suppression abilities of SURF imaging. Moreover, it is shown that the methods might be utilized to reduce the accumulated near-field energy of the SURF transmit-beam relative to its imaging region energy. The adjustments presented may therefore potentially be utilized to attain a slightly better general suppression of multiple scattering and multiple reflection noise compared with non-adjusted SURF reverberation-suppression imaging.

A method of acoustic imaging that potentially can improve the diagnostic capabilities of medical ultrasound is presented. The method, given the name SURF (Second order UltRasound Field) imaging, is achieved by processing the received signals from transmitted dual frequency band pulse complexes with at least partly overlapping high frequency (HF) and low frequency (LF) pulses. The transmitted HF pulses are used for image reconstruction, whereas the transmitted LF pulses are used to manipulate the elastic properties of the medium observed by the HF imaging pulses. The present paper discusses fundamental concepts in relation to the use of dual frequency band pulse complexes for medical ultrasound imaging.

A method that uses dual-frequency pulse complexes of widely separated frequency bands to suppress noise caused by multiple scattering or multiple reflections in medical ultrasound imaging is presented. The excitation pulse complexes are transmitted to generate a second order ultrasound field (SURF) imaging synthetic transmit beam. This beam has reduced amplitude near the transducer, which illustrates the multiple scattering suppression ability of the imaging method. Field simulations solving a nonlinear wave equation are used to calculate SURF imaging beams, which are compared with beams for pulse inversion (PI) and fundamental imaging. In addition, a combined SURF and PI beam generation is described and compared with the beams mentioned above. A quality ratio, relating the energy within the near-field to that within the imaging region, is defined and used to score the multiple scattering and multiple reflection suppression abilities when imaging with the different beams. The realized combined SURF-PI beam scores highest, followed by SURF, PI (that score equally well), and the fundamental. The amplitude in the imaging region and therefore also the SNR is highest for the fundamental followed by SURF, PI, and SURF-PI. The work hence indicates that when substituting PI for SURF, one may trade increased SNR into use of increased imaging frequencies without loss of multiple scattering and multiple reflection noise suppression.

A contrast agent detection method is presented that potentially can improve the diagnostic significance of ultrasound contrast agents. Second order ultrasound field (SURF) contrast imaging is achieved by processing the received signals from transmitted dual frequency band pulse complexes with overlapping high-frequency (HF) and low-frequency (LF) pulses. The transmitted HF pulses are used for image reconstruction, whereas the transmitted LF pulses are used to manipulate the scattering properties of the contrast agent. In the present paper, we discuss how SURF contrast imaging potentially can overcome problems and limitations encountered with available contrast agent detection methods, and we give a few initial examples of in vitro measurements. With SURF contrast imaging, the resonant properties of the contrast agent may be decoupled from the HF imaging pulses. This technique is thus especially interesting for imaging contrast bubbles above their resonance frequency. However, to obtain adequate specificity, it is typically necessary to estimate and correct for accumulative nonlinear effects in the forward wave propagation.

An annular array design method is described and used for definition of an array proposal. The geometric pre-focus, realized by curving or use of an acoustic lens, varies among the annuli. Element sizes and geometric pre-focus depths are determined by a maximum allowed phase-shift within the active depth region of each element on receive, resulting in fewer elements or larger apertures compared with the standard equal area design. The method allows combination of large aperture and high frequency with a large receive depth of field. The developed design rules are used to define an array for imaging within the frequency interval [7.5, 15] MHz. Its total aperture diameter is 22 mm and the thinnest element is 0.23 mm wide. Receive beams resulting from this array are simulated. The beams and their sidelobe-to-mainlobe energy ratios are compared with an ideally focused reference where there are no phase shifts over the elements. Within nearly the entire depth of field, the sidelobe-to-mainlobe energy ratio is less than 5 dB higher than for the ideal reference.

Presented here is a characterization of aberration in medical ultrasound imaging. The characterization is optimal in the sense of maximizing the expected energy in a modified beamformer output of the received acoustic backscatter. Aberration correction based on this characterization takes the form of an aberration correction filter. The situation considered is frequently found in applications when imaging organs through a body wall: aberration is introduced in a layer close to the transducer, and acoustic backscatter from a scattering region behind the body wall is measured at the transducer surface. The scattering region consists of scatterers randomly distributed with very short correlation length compared to the acoustic wavelength of the transmit pulse. The scatterer distribution is therefore assumed to be delta correlated. This paper shows how maximizing the expected energy in a modified beamformer output signal naturally leads to eigenfunctions of a Fredholm integral operator, where the associated kernel function is a spatial correlation function of the received stochastic signal. Aberration characterization and aberration correction are presented for simulated data constructed to mimic aberration introduced by the abdominal wall. The results compare well with what is obtainable using data from a simulated point source.

Based on new advancements in digital technology, we developed a PC- and DSP-based measurement and control system for isolated papillary muscle experiments. High flexibility was obtained through a three level control. Length or force was controlled real-time with a sample frequency of 5000 Hz. Muscle length and up to three segment lengths were measured simultaneously and each of these lengths could be chosen as feedback variable. Individual algorithms were implemented for different twitch types. Batches of twitches were organized in experiment protocols. The system included a new twitch type, namely a controlled auxotonic twitch. In this twitch, the muscle acted against a virtual ideal spring, giving a proportional change in developed force and shortening. The value of the virtual spring constant could be set on-line or defined in the experiment protocol. An increasing virtual spring constant represented a smooth transition from isotonic to isometric conditions., (Copyright 2000 Academic Press.)

Venodilatation with consequent reduction in left ventricular filling and end-diastolic wall stress is an important mechanism for the beneficial effects of nitroglycerin in ischemic heart disease and in left ventricular failure. The effects of sublingual nitroglycerin on arterial pulsatile hemodynamics are less well defined. Doppler echocardiography and the calibrated subclavian artery pulse tracing were used to assess hemodynamics in subjects with sustained arterial hypertension (n = 25) before and 5 to 10 minutes after sublingual deposition of 0.5 mg glyceryl trinitrate. Aortic characteristic impedance was calculated by averaging the modulus of the input impedance (ratio of pressure to flow) at high frequencies and by calculating the ratio of pressure and flow increments during upstroke. The pressure wave was split into forward and backward components, and the reflection coefficient (the ratio of backward to forward pressures) was calculated. Parameters of the arterial bed were estimated by using 2- and 3-element Windkessel models. Nitroglycerin delayed the return of arterial wave reflections by 17% (P =.02) and increased aortic characteristic impedance by 20% (P =. 01), but it did not influence total arterial compliance. Mean arterial pressure decreased 7% (P =.0001), but pulse pressure did not change. Stroke volume and the acceleration time of aortic root flow decreased by 13% (P =.0001) and 8% (P =.01), respectively. Cardiac output decreased 7% (P =.01), despite an increase in heart rate of 10% (P =.0001). Peripheral resistance tended to decrease (4%, P =.06). Thus, in subjects with sustained hypertension, sublingual nitroglycerin dilates peripheral, predominantly muscular arteries with a subsequent delayed return of reflected pressure waves. Reflex activation of the sympathetic nervous system with consequent increased acceleration of left ventricular ejection seems to counteract the effect of reduced mean arterial pressure (distending pressure) with respect to the "stiffness" of the aorta.

The aim was to investigate determinants of total arterial compliance in healthy humans. Estimates of aortic root pressures and flow were obtained non-invasively with the calibrated subclavian artery pulse tracing and Doppler echocardiography in 37 males (27-76 years) and 45 females (20-77 years). Total arterial compliance, estimated using a three-element vascular model, correlated positively with body height (r = 0.45, p < 0.01) and acceleration time of aortic root flow (r = 0.32, p < 0.01) and inversely with age (r = -0.34, p < 0.05), heart rate (r = -0.33, p < 0.01), and mean arterial pressure (r = -0.51, p < 0.01). Multivariate analysis indicated that height and heart rate contributed most to the prediction of total arterial compliance. The inclusion of mean arterial pressure within the model significantly reduced the contribution of age, but not that of body height and heart rate. After adjustment for height and heart rate, total arterial compliance did not differ significantly between gender. Thus, total arterial compliance, as assessed in this study, seems to reflect both arterial capacity and viscoelastic properties of the arterial wall. Differences in body size, heart rate and mean arterial pressure should be considered when comparing total arterial compliance in different groups.

Six relevant computer-implemented reference systems for three-dimensional quantitative assessment of left ventricular wall motion abnormalities were compared with visual wall motion analysis of two-dimensional images. Endocardial borders were traced in three apical echocardiographic views at end-diastole and end-systole in 10 patients with myocardial infarction and 5 healthy subjects, and three-dimensional reconstruction of endocardial surfaces was performed. End-diastolic and end-systolic surfaces were aligned in a common axis system depending on the reference system, and systolic wall motion was assessed at 1,024 points on the endocardial surface. The localization of abnormal wall motion was displayed in bull's-eye maps, and the area was determined as a percentage of total endocardial area. For each reference system, the segmental concordance between three-dimensional computerized and visual assessment was determined. The best agreement between computerized and visual analysis was obtained with a reference system based on wall motion towards the major ventricular axis, whereas the poorest result was obtained using the center of left ventricular cavity as reference. Correlation between the estimated area of wall motion abnormality and visually determined wall motion score index was best using the aligned center of mitral valve plane as reference (r = .92).

Systemic arterial properties and left ventricular function were assessed by Doppler echocardiography and a calibrated subclavian artery pulse tracing early (5 weeks) and late (27 months) after a first acute myocardial infarction in 19 patients aged 44-77 years and in healthy subjects matched for age, gender, and arterial blood pressure. Total arterial compliance (3-element windkessel model) was reduced by 26% (p < 0.001) from early to late assessment, and left-ventricular end-diastolic and end-systolic volumes were increased by 11 and 18%, respectively (p < 0.05). Peripheral resistance and characteristic impedance were not significantly changed. The healthy matched subjects had arterial compliance similar to patients at early assessment, but tended to be higher at late. Thus, 2.3 years after a first acute myocardial infarction with moderate left ventricular dilatation, arterial distensibility was significantly decreased whereas peripheral resistance was not changed.

This study, which includes seven patients, illustrates some potential values of the interactive use of ultrasound technology prior to, during and after brain tumour resection. Ultrasound B-scan and colour flow imaging were applied during open surgery using a cardiac scanner in the 3.25-7.5 MHz frequency range and an intravascular scanner with catheters at 10, 20 and 30 MHz. The tumour and vital blood vessels were localized prior to resection using low frequency imaging from the brain surface. High frequency, high resolution close-up imaging was applied during and after resection in order to identify remaining tumour tissue, as well as to detect blood vessels in the vicinity of the resection wall. The study also demonstrates that the tumour and surgical tools such as, for example, bipolar diathermy, acoustic aspirator or biopsy forceps,can be visualized simultaneously. This simplifies the localization of remaining tumour tissue.

Left ventricular performance depends not only on myocardial state, but also on the properties of the systemic arterial tree. These properties can be assessed from recordings of aortic root pressure and flow by the use of appropriate vascular models. Noninvasive estimates of aortic root pressure and flow can be obtained by the combined use of calibrated external subclavian artery pulse tracing and Doppler echocardiography. With recent advances in computer technology, estimation of model parameters are thus accessible in the clinical setting. We discuss the suitability of different parametric vascular models together with methods for adapting these models to the measured aortic root pressure. We compared the results obtained with simple vascular models (three-component modified Windkessel models) with those of five-component models. The simpler models gave less accurate approximation of the measured pressure waveform, but for a representative set of aortic root pressure and flow data, the simpler models provided adequate estimates of the peripheral arterial resistance, the total arterial compliance, and the proximal aortic area compliance. Furthermore, the simpler models are robust for measurement noise with simple estimation algorithms. Distal arterial pressure and flow waveforms are more oscillatory, and for these the five-component model has more robust estimation schemes with more accurate estimated parameters. Hence, we conclude that for clinical noninvasive assessment of aortic vascular properties, the simpler three-component models provide adequate information. For assessment of the peripheral arteries with large oscillations in the flow, the three-component models can give more than 10% error in the compliance estimate and more complex models can be appropriate.

A method for quantitative LV wall motion analysis based on 3-D reconstruction of the LV endocardial surface is presented. The reconstruction is based on a minimum of three transthoracic apical 2-D cineloops of the LV, digitally transferred from the ultrasound scanner to a computer. Images are obtained by rotating the transducer around the LV long axis. Endocardial borders are traced with an automatic edge detection algorithm with manual correction. These borders are used with a specially designed computer algorithm for reconstruction of LV cavity 3-D shape, and LV volumes, ejection fraction, and endocardial surface area can be determined. The end-diastolic and end-systolic endocardial surfaces are compared for analysis of regional wall motion. A threshold value is selected to discriminate between normal and abnormal wall motion. Regional wall motion abnormalities are displayed in a bull's eye plot, and the corresponding endocardial surface area is expressed in percent of the total endocardial area. Phase analysis is performed from reconstruction of the endocardial surface throughout the cardiac cycle, and displays regions with abnormal wall motion as being out of phase with LV volume variation. Thus, LV 3-D reconstruction performed by this method can be used for quantitative analysis of wall motion in several clinical situations, and due to the simplicity of processing the data, can be useful outside the research laboratory.

The regurgitant volume and regurgitant orifice area as well as total peripheral resistance and arterial compliance were estimated in a cardiovascular hydromechanical simulator and in 10 patients with aortic regurgitation. A parameter estimation procedure based on a simple model of the cardiovascular system, Doppler measurements of the regurgitant jet, aortic systolic flow, and systolic and diastolic blood pressures was used. In the cardiovascular simulator the estimated regurgitant orifice area was compared with the size of a hole in the disk of a mechanical aortic valve. In the patients the regurgitant fraction was compared with semiquantitative grading from echocardiography routinely performed in our laboratory. In the hydromechanical simulator, the estimated regurgitant orifice area of 26.5 +/- 3.5 (SD) mm2 (n = 9) was not different from the true value of 24 mm2. In the patients there was a fair relationship between the estimated regurgitant fraction and the semiquantitative grading. The estimated regurgitant orifice areas varied between 1.6 and 31.2 mm2. The estimated mean values of total peripheral resistance and arterial compliance were 1.67 +/- 0.55 mmHg.s.ml-1 and 1.30 +/- 0.42 ml/mmHg, respectively.

In the fetus, the umbilical vein is directly linked to the inferior vena cava by the narrow ductus venosus. Thus, the ductus venosus blood velocity probably reflects the pressure gradient between the umbilical vein and the central venous system. In a longitudinal study that included 29 normal fetuses, pulsed Doppler velocimetry was carried out in the umbilical vein and the ductus venosus during the last half of the pregnancy. By applying the Bernoulli equation, we estimated the pressure gradient across the ductus venosus to vary between 0-3 mm Hg during the heart cycle; it remained within those ranges during gestational weeks 18-40. During fetal inspiratory movement, pressure gradients up to 22 mm Hg were estimated. The estimated ductus venosus pressure gradient seems to be within ranges compatible with known umbilical venous pressures, and may provide a new opportunity to understand central venous hemodynamics and respiratory force in the fetus once methodological limitations are controlled.

Aortic root pressure and flow data can be used to assess left ventricular (LV) performance and properties of the systemic arterial tree. The calibrated subclavian arterial pulse trace was combined with echocardiographic imaging and Doppler velocity recordings to obtain noninvasive estimates of aortic root pressure and flow in 8 healthy subjects (group A), 12 patients with recent myocardial infarction (group B), and 8 with healed myocardial infarction and a dilated left ventricle (group C). The pressure and flow data were transferred to a computer and processed in specially designed software, including a new procedure for estimation of 3-element windkessel model parameters. There were no significant group differences for either aortic root pressure estimates or heart rate. In groups B and C, stroke and cardiac indexes were lower and total peripheral resistance higher than in group A. There were no group differences in the model estimates of total arterial compliance, whereas the characteristic impedance was greater in group C than in A, indicating a less compliant aorta in C. Both LV total and steady power were less in groups B and C than in A, whereas no group difference was found for percent oscillatory power. The reproducibility for recording was good for the aortic root pressure estimates, and lower for the derived parameters (stroke and cardiac indexes, windkessel model parameters and LV power), whereas that for interpretation was generally good. This method provides a unique noninvasive access to important parameters of LV function and the systemic circulation.

The intravascular ultrasonographic findings in normal and diseased veins after transfemoral catheterization of 25 patients are presented. The iliac veins, the inferior and superior vena cava, the renal veins, the right atrium, both brachiocephalic veins, and the right internal jugular vein were studied. In 4 cases valves or valve-like structures were observed. Anatomic variants such as spurs and webs were seen in 3 and mural thrombi or postthrombotic wall changes in 4 patients. In one case a sphincter-like ostium venae cavae was observed. In 2 patients thin filaments within the right atrium, most likely a Chiari net, were seen. Two patients had an abnormal, stratified "artery-like" vessel wall structure. This new imaging modality has several potential applicabilities in the veins and may contribute new information about anatomy and function of the venous system. It provides cross-sectional in vivo visualization and the demonstration of motility of small intraluminal structures which cannot be revealed by traditional diagnostic methods. Because of the wide range of anatomic variation in the venous system, knowledge of its normal intravascular ultrasonographic appearance is a prerequisite for further clinical investigations.

In vitro experiments were performed in order to investigate the appearance of different types of central venous catheters at intravascular ultrasonography. The experiments were repeated with artificially produced thrombi which were made adherent to the catheter wall. All thrombi larger than 1 mm could be identified. In a clinical study including 12 patients who had a central venous catheter, transfemoral intravascular ultrasonography was performed. The catheters had been in place for an average period of 54 days (range 1-360 days). In 3 patients a catheter thrombus, mural thrombus, or occlusive vein thrombosis was found. In 2 of these patients the catheter was occluded, in the 3rd patient it was malpositioned into the contralateral brachiocephalic vein. There were no complications following the ultrasonographic procedures. Mean catheterization time was 7.5 min (range 3-20 min). The advantages of this new method compared with conventional phlebographic studies and its impact on further clinical investigations are discussed.

In 22 individuals (mean age 52 years) the ultrasonographic images of arteries defined as normal by arteriography were studied and related to the age and medical history of the patients. The series was divided into 2 groups: patients with clinical manifestation of atherosclerosis and patients without a history of arterial disease. The study included 6 young patients (mean age 14 years) referred for angiographic documentation of abolished intracranial circulation. A typical 3-layered appearance of the arterial wall was found in young healthy individuals as well as in adult and elderly subjects. There was no difference in the ultrasonographic appearance of muscular and elastic arteries. In patients with extensive obstructive atherosclerosis affecting other parts of the arterial tree, a segment of the iliac artery can have the same appearance as seen in young healthy individuals. There are indications that severe hypertension can result in a thickening of the middle low-echogenic layer of the arterial wall. In patients with chronic renal insufficiency, small calcifications in the middle layer were a typical finding.

We have developed a method to calculate flow noninvasively in blood vessels using color Motion-mode (M-mode) and computer postprocessing. The velocity of each point in the cross-sectional area of the vessel was found from the color M-mode recording by correcting for angle both distances and velocities and by assuming a symmetrical circular velocity field. Volume flow was then found by integrating the velocity field at 5-ms intervals through the cardiac cycle. In a cardiovascular hydromechanical model, a correlation of 0.99 and p value of less than 0.001 were found between estimated and measured flow in the model (n = 8). In 20 healthy individuals, we made 31 investigations in the common carotid (CCA), internal carotid (ICA), and external carotid (ECA) artery, comparing flow in the CCA with the added flow in the ICA and ECA. The values (CCA versus ICA + ECA) correlated with r = 0.91 and p less than 0.01. Repeated investigations (n = 8) in one individual gave flow estimates of 495 +/- 50 ml/min in the CCA, 304 +/- 45 ml/min in the ICA, and 165 +/- 37 ml/min in the ECA (means +/- SD). This article shows that this system can make accurate estimation of blood flow to the brain noninvasively.

The velocity distribution in the aortic anulus is commonly assumed to be uniform. A skewed velocity profile may have consequences for the accuracy of volume flow estimates by the Doppler echocardiographic technique. To assess this issue, the velocity distribution in the aortic anulus in 12 normal subjects was studied by computer analysis of digital velocity data from two-dimensional Doppler ultrasound flow maps. The velocity profiles in the aortic anulus were found to be flat but slightly skewed, with the highest velocities toward the septum. There was little interindividual variation. Our findings imply that the centerline velocity is the best estimate for the spatial mean velocity at the aortic anulus in normal subjects. The importance of this finding in patients is unknown. In normal subjects, the results suggest that stroke volume might be overestimated by approximately 15% by Doppler echocardiography if the cross-sectional velocity profile is not accounted for.

Intra-arterial ultrasound is a new real-time imaging technique using a miniaturized transducer in a catheter to image diseased arteries. The small size and close proximity to the structures being imaged allow the use of frequencies from 20-40 MHz, resulting in high resolution images. In addition to the stenotic lumen, it is possible to examine the composition and eccentricity of the plaque, as well as structures outside of the vessel. Such information can be used for planning and evaluating vascular interventions. The addition of Doppler measurements allows the evaluation of function as well as anatomy. Research applications include studies of lesion progression, measurement of arterial elasticity, quantitative blood flow velocities and study of intra-arterial flow patterns. Although this technique is in its infancy, it is highly probable that it will prove to be a useful aid to the vascular surgeon.

Intravascular ultrasound is a new method for visualizing the details of vascular pathology, providing high resolution images of plaque and thrombus. This review summarizes the potential applications of ultrasound imaging in the guidance of balloon angioplasty, atherectomy, laser ablation and stenting. Ultrasound differs from angiography and angioscopy in its ability to penetrate below the surface of the vessel lumen, demonstrating specific aspects about the distribution and composition of plaque. Because the different layers of the arterial wall have different acoustic properties, ultrasound catheters are able to define the layers of normal wall in comparison with plaque. Particularly in combination with therapeutic techniques designed to remove or ablate plaque, ultrasound may prove useful in maximizing the amount of plaque treated and minimizing trauma to normal vessel wall components. Combined imaging/therapeutic devices are in the pilot phase of development and show promise for enhancing the safety and efficacy of the catheter devices.

Twenty nine patients (aged from three months to 37 years) with confirmed or suspected ventricular septal defects were studied separately by three examiners who used colour flow mapping and imaging, or continuous wave Doppler and imaging, or a combined reference examination. Colour flow mapping identified 19 of the 25 patients with a ventricular septal defect, continuous wave Doppler echocardiography identified 18, and the combined reference examination identified 24. Two of four patients without ventricular septal defect had a false positive result with colour flow mapping and none had a false positive result with continuous wave Doppler examination. During the reference examination continuous wave Doppler identified 24 patients with ventricular septal defects and colour flow mapping identified 23. In two patients a second ventricular septal defect was found by colour flow mapping, and confirmed by continuous wave Doppler. There was no significant difference in time to diagnosis between the two techniques. Colour flow mapping aids identification of multiple ventricular septal defects but is not faster and has lower specificity than continuous wave Doppler. A combination of the two techniques gave the highest sensitivity and specificity.

Although we are able to identify many tissue types based on the screen image in intravascular ultrasound, there is additional information in the ultrasound signal which could be of assistance in characterization and identification of tissue. Intravascular ultrasound has several special characteristics which affect tissue characterization. These include the high transducer frequency, small transducers, short and relatively uniform path to the tissue, and limited tissue types to identify. These characteristics influence the results obtained by absolute backscatter, local statistics, frequency dependent backscatter, and angle dependency of backscatter. These effects are both positive and negative, and in many cases can be observed in clinical imaging. Another area of tissue characterization which can be performed with ultrasound is measurement of arterial wall elasticity. This can be of importance in the evaluation of mechanisms of dilatation, and the potential for complications.

Significant circulatory changes occur in microgravity and gas bubbles may be present in the circulation as a result of decompression during EVA. A system for the non-invasive evaluation of circulatory changes and gas bubbles in the circulation is described. This system is based on an ultrasonic scanning and Doppler system (CFM 700(750), Vingmed Sound, Horten Norway) together with programs to transmit the data to a Macintosh [correction of Mackintosh] II computer. A method for measuring pulsatile blood pressure non-invasively is also included. On the computer, programs for the calculation of cardiovascular parameters and the analysis of ultrasonic images containing gas bubbles have been developed.

A method for noninvasive estimation of regurgitant orifice and volume in aortic regurgitation is proposed and tested in anesthetized open chested pigs. The method can be used with noninvasive measurement of regurgitant jet velocity with continuous wave ultrasound Doppler measurements together with cuff measurements of systolic and diastolic systemic pressure in the arm. These measurements are then used for parameter estimation in a Windkessel-like model which include the regurgitant orifice as a parameter. The aortic volume compliance and the peripheral resistance are also included as parameters measurements in the open chest pigs are used. Electromagnetic flow measurements in the ascending aorta and pulmonary artery are used for control, and a correlation between regurgitant volume obtained from parameter estimation and electromagnetic flow measurements of 0.95 over a range from 2.1 to 17.8 mL is obtained.

One of the most compelling practical applications for intravascular ultrasound imaging is in enhancing the safety and efficacy of the second-generation catheter devices designed to ablate or remove plaque. Initial studies have shown that intravascular ultrasound is well suited to demonstrate the amount of atheroma present in a vessel, and the distribution within the vessel wall at any given point. Further clinical studies are required to determine whether more complete debulking of atheroma, guided by ultrasound imaging, has a favorable impact in reducing the rates of acute closure and restenosis following the procedure.

We have developed a method to quantify aortic regurgitant orifice and volume, based on measurements of the velocity of the regurgitant jet, aortic systolic flow, the systolic and diastolic arterial pressures, a Windkessel arterial model, and a parameter estimation technique. In six pigs we produced aortic regurgitant flows between 2.1 and 17.8 ml per beat, i.e. regurgitant fractions from 0.06 to 0.58. Pulmonary and aortic flows were measured with electromagnetic flow probes, aortic pressure was measured invasively, and the regurgitant jet velocity was obtained with continuous-wave Doppler. The parameter estimation procedure was based on the Kalman filter principle, resulting primarily in an estimate of the regurgitant orifice area. The area was multiplied by the velocity integral of the regurgitant jet to estimate regurgitant volume. A strong correlation was found between the regurgitant volumes obtained by parameter estimation and the electromagnetic flow measurement. These results from our study in pigs suggest that it may be possible to quantify regurgitant orifice and volume in patients completely noninvasively from Doppler and blood pressure measurements.

Three methods for measuring arterial compliance when aortic regurgitation is present are examined. The first two methods are based on a Windkessel model composed of two elements, compliance C and resistance R. Arterial compliance was estimated from diastolic pressure waveforms and diastolic regurgitant flow for one method, and from systolic aortic pressure waveforms and systolic flow for the other method. The third method was based on a three-element Windkessel model, composed of characteristic resistance r, compliance C and resistance R. In this method arterial compliance was calculated by adjusting the model to the modulus and phase of the first harmonic term of the aortic input impedance. The three methods were compared and validated in six anaesthetised pigs over a broad range of aortic pressures. The three methods were found to give quantitatively similar estimates of arterial compliance at mean aortic pressures above 60 mm Hg. Below 60 mm Hg, estimates of arterial compliance varied widely, probably because of poor validity of the Windkessel models in the low pressure range.

To determine the value of a recently developed 7.5 MHz annular array two-dimensional and color flow Doppler transducer for examination of the proximal parts of the left coronary artery, 25 patients were studied immediately after coronary artery bypass surgery, and the findings were compared with preoperative coronary angiograms. With two-dimensional imaging, the left main coronary artery was visualized in 22 patients (88%), left anterior descending in 13 patients (52%), and circumflex in 22 patients (88%). Stenoses were correctly identified in four of four left main coronary arteries, in five of seven left anterior descending arteries, and in none of four left circumflex arteries. Adding color flow to two-dimensional imaging in 20 patients, we found a disturbed flow signal, as a sign of stenosis, in five of five left anterior descending artery and two of four left circumflex artery stenoses. We concluded that these initial findings with this new 7.5 MHz annular array two-dimensional and color flow Doppler transducer, are promising in imaging and detection of stenoses in the proximal parts of the left coronary artery.

The pattern of acoustic speckle present in ultrasonic images of tissue may be affected by pathological changes in the tissue. To investigate the possibility for such an effect in dilated cardiomyopathy, we examined acoustic micrographs of frozen sections of normal (autopsy) and myopathic (transplant recipient) human myocardium. The resulting images were digitized, and the major axis autocorrelation length calculated for each image. For the normal specimens (n = 75, four patients), the mean autocorrelation length was 37 +/- 18 microns, with the maximum value of 92 microns. The myopathic specimens (n = 64, four patients) had a mean of 52 +/- 19 microns, with a maximum of 100 microns. We conclude that the changes in structure between normal and myopathic myocardium are significant (p less than 0.001), but on so small a scale in relation to the wave length of clinical ultrasound that there will only be changes in the intensity of the backscattered signal, not the pattern of speckle.

Systolic pressure in the pulmonary artery was estimated from the interval between pulmonary valve closure and tricuspid valve opening, and the heart rate using a nomogram previously described. The timing of valve movements was recorded by Doppler ultrasound. The estimated pressure correlated well with that obtained at catheterisation in 45 of 48 patients with pulmonary hypertension. Instantaneous variations in pressure and changes with treatment and during exercise could be measured. The method was easy to apply in all age groups, and was found useful both in detecting pulmonary hypertension and in the follow-up of patients. It may help to determine the optimal time for surgery or the effect of treatment.

To study aortic velocities in the fetus, a newly developed multirangegated Doppler velocimeter was combined with a commercial B-mode linear-array apparatus. Spectrum analysis of the Doppler shift signals was performed. The signals with the highest frequencies were selected for hard-copy, and integrated with a digitizer. In the first part of the study, the reproducibility of the method was established by serial measurements of aortic velocity in 7 near-term fetuses. It proved sufficient to evaluate 5 successive heart-cycles. The mean coefficient of variation was 5% (mean number of recordings evaluated 7.5). In the second part of the study, possible influence of aortocaval compression on fetal aortic velocity indicative of changes in fetal cardiac output, was investigated in 10 pregnant women with no symptoms of supine hypotension. Doppler monitoring of the material cardiac output from the suprasternal notch was added to the set-up described to study the supine reduction of cardiac output frequently described in pregnant women. No significant change was found either in the maternal or in the fetal circulation.

Intra-arterial ultrasonic imaging has several features which affect the feasibility of clinical tissue characterization when compared with trans-thoracic ultrasound. The short distance from transducer to tissue, fluid path, high frequencies, and special characteristics of the tissues of interest all contribute to making practical tissue characterization by measurement of the backscattered signal more probable in intra-arterial imaging. The properties of backscattered ultrasound, and methods of characterizing such signals, are discussed with special reference to intra-arterial applications.

A Doppler velocity meter for measuring blood flow velocity in the human aorta is described. Using pulsed ultrasound, this instrument allows the velocity to be measured at selected depths. The instrument has been tested in laboratory experiments, and appears to give accurate estimates of mean flow velocity for both steady and pulsatile flows. Flow velocities and estimates of stroke volume have been obtained from the ascending aorta in 18 patients. It is suggested that at present only relative values for flow and flow velocity can be measured. A method for obtaining absolute values for these parameters, based on scanning in the aortic arch, is proposed.

An ultrasonic Doppler instrument capable of measuring mean and maximum velocities inside a small sample volume is presented. The instrument has been used for determining velocities in normal and diseased heart valves. A method is described for identifying the different heart valves, based on their relation to one another as well as the form of the velocity curve. The pressure drop across the mitral valve can be determined from the maximum velocity and the mean velocity can be used to determine the degree of aortic insufficiency. Recordings of mean and maximum velocities can give an indication of the form of the whole spectrum, thus making complete frequency analysis unnecessary for most purposes.

Instantaneous cross sectional flow velocity profiles from early mitral flow in 10 healthy men were constructed by time interpolation of the velocity data from each point in sequentially delayed two dimensional digital Doppler ultrasound maps. This interpolation allows correction of the artificially produced skewness of velocities across the flow sector caused by the time taken to scan the flow sector for velocity recording of pulsatile blood flow. These results suggested that early mitral flow studied in an apical four chamber view is variably skewed both at the leaflet tips and at the annulus. The maximum flow velocity overestimated the cross sectional mean velocity at the same time by a factor of 1.2-2.2. Also the maximum time velocity integral overestimated the cross sectional mean time velocity integral to the same extent. This cross sectional skew must be taken into account when calculation of blood flow is based on recordings with pulsed wave Doppler ultrasound from a single sample volume.