Atrial fibrillation (AF) is the most common cardiac arrhythmia and is normally treated by RF ablation. Intracardiac echography (ICE) is widely employed during RF ablation procedures to guide the electrophysiologist in navigating the ablation catheter, although only 2-D probes are currently clinically used. A 3-D ICE catheter would not only improve visualization of the atrium and ablation catheter, but it might also provide the 3-D mapping of the electromechanical wave (EW) propagation pattern, which represents the mechanical response of cardiac tissue to electrical activity. The detection of this EW needs 3-D high-frame-rate imaging, which is generally only realizable in tradeoff with channel count and image quality. In this simulation-based study, we propose a high volume rate imaging scheme for a 3-D ICE probe design that employs 1-D micro-beamforming in the elevation direction. Such a probe can achieve a high frame rate while reducing the channel count sufficiently for realization in a 10-Fr catheter. To suppress the grating-lobe (GL) artifacts associated with micro-beamforming in the elevation direction, a limited number of fan-shaped beams with a wide azimuthal and narrow elevational opening angle are sequentially steered to insonify slices of the region of interest. An angular weighted averaging of reconstructed subvolumes further reduces the GL artifacts. We optimize the transmit beam divergence and central frequency based on the required image quality for EW imaging (EWI). Numerical simulation results show that a set of seven fan-shaped transmission beams can provide a frame rate of 1000 Hz and a sufficient spatial resolution to visualize the EW propagation on a large 3-D surface. @en

Although high-frequency ultrasound imaging is gaining attention in various applications, hardly any ultrasound contrast agents (UCAs) dedicated to such frequencies (>15 MHz) are available for contrast-enhanced ultrasound (CEUS) imaging. Moreover, the composition of the limited commercially available UCAs for high-frequency CEUS (hfCEUS) is largely unknown, while shell properties have been shown to be an important factor for their performance. The aim of our study was to produce UCAs in-house for hfCEUS. Twelve different UCA formulations A-L were made by either sonication or mechanical agitation. The gas core consisted of C4F10 and the main coating lipid was either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC; A-F formulation) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC; G-L formulation). Mechanical agitation resulted in UCAs with smaller microbubbles (number weighted mean diameter ∼1 μm) than sonication (number weighted mean diameter ∼2 μm} ). UCA formulations with similar size distributions but different main lipid components showed that the DPPC-based UCA formulations had higher nonlinear responses at both the fundamental and subharmonic frequencies in vitro for hfCEUS using the Vevo2100 high-frequency preclinical scanner (FUJIFILM VisualSonics, Inc.). In addition, UCA formulations F (DSPC-based) and L (DPPC-based) that were made by mechanical agitation performed similar in vitro to the commercially available Target-Ready MicroMarker (FUJIFILM VisualSonics, Inc.). UCA formulation F also performed similar to Target-Ready MicroMarker in vivo in pigs with similar mean contrast intensity within the kidney ( n = 7 ), but formulation L did not. This is likely due to the lower stability of formulation L in vivo. Our study shows that DSPC-based microbubbles produced by mechanical agitation resulted in small microbubbles with high nonlinear responses suitable for hfCEUS imaging.@en

In the above article [1], the authors regret that there was a mistake in calculating the mol% of the microbubble coating composition used. For all experiments, the unit in mg/mL was utilized and the conversion mistake only came when converting to mol% in order to define the ratio between the coating formulation components. The correct molecular weight of PEG-40 stearate is 2046.54 g/mol [2], [3], not 328.53 g/mol. On page 556, Table I should read as shown here.@en

Angiogenesis is a critical feature of plaque development in atherosclerosis and might play a key role in both the initiation and later rupture of plaques. The precursory molecular or cellular pro-angiogenic events that initiate plaque growth and that ultimately contribute to plaque instability, however, cannot be detected directly with any current diagnostic modality. This study was designed to investigate the feasibility of ultrasound molecular imaging of endothelial αvβ3 expression in vitro and in vivo using αvβ3-targeted ultrasound contrast agents (UCAs). In the in vitro study, αvβ3 expression was confirmed by immunofluorescence in a murine endothelial cell line and detected using the targeted UCA and ultrasound imaging at 18-MHz transmit frequency. In the in vivo study, expression of endothelial αvβ3 integrin in murine carotid artery vessels and microvessels of the salivary gland was quantified using targeted UCA and high-frequency ultrasound in seven animals. Our results indicated that endothelial αvβ3 expression was significantly higher in the carotid arterial wall containing atherosclerotic lesions than in arterial segments without any lesions. We also found that the salivary gland can be used as an internal positive control for successful binding of targeted UCA to αvβ3 integrin. In conclusion, αvβ3-targeted UCA allows non-invasive assessment of the expression levels of αvβ3 on the vascular endothelium and may provide potential insights into early atherosclerotic plaque detection and treatment monitoring.@en

Angiogenesis is a critical feature of plaque development in atherosclerosis and might play a key role in both the initiation and later rupture of plaques. The precursory molecular or cellular pro-angiogenic events that initiate plaque growth and that ultimately contribute to plaque instability, however, cannot be detected directly with any current diagnostic modality. This study was designed to investigate the feasibility of ultrasound molecular imaging of endothelial αvβ3 expression in vitro and in vivo using αvβ3-targeted ultrasound contrast agents (UCAs). In the in vitro study, αvβ3 expression was confirmed by immunofluorescence in a murine endothelial cell line and detected using the targeted UCA and ultrasound imaging at 18-MHz transmit frequency. In the in vivo study, expression of endothelial αvβ3 integrin in murine carotid artery vessels and microvessels of the salivary gland was quantified using targeted UCA and high-frequency ultrasound in seven animals. Our results indicated that endothelial αvβ3 expression was significantly higher in the carotid arterial wall containing atherosclerotic lesions than in arterial segments without any lesions. We also found that the salivary gland can be used as an internal positive control for successful binding of targeted UCA to αvβ3 integrin. In conclusion, αvβ3-targeted UCA allows non-invasive assessment of the expression levels of αvβ3 on the vascular endothelium and may provide potential insights into early atherosclerotic plaque detection and treatment monitoring.@en

Angiogenesis is a critical feature of plaque development in atherosclerosis and might play a key role in both the initiation and later rupture of plaques. The precursory molecular or cellular pro-angiogenic events that initiate plaque growth and that ultimately contribute to plaque instability, however, cannot be detected directly with any current diagnostic modality. This study was designed to investigate the feasibility of ultrasound molecular imaging of endothelial αvβ3 expression in vitro and in vivo using αvβ3-targeted ultrasound contrast agents (UCAs). In the in vitro study, αvβ3 expression was confirmed by immunofluorescence in a murine endothelial cell line and detected using the targeted UCA and ultrasound imaging at 18-MHz transmit frequency. In the in vivo study, expression of endothelial αvβ3 integrin in murine carotid artery vessels and microvessels of the salivary gland was quantified using targeted UCA and high-frequency ultrasound in seven animals. Our results indicated that endothelial αvβ3 expression was significantly higher in the carotid arterial wall containing atherosclerotic lesions than in arterial segments without any lesions. We also found that the salivary gland can be used as an internal positive control for successful binding of targeted UCA to αvβ3 integrin. In conclusion, αvβ3-targeted UCA allows non-invasive assessment of the expression levels of αvβ3 on the vascular endothelium and may provide potential insights into early atherosclerotic plaque detection and treatment monitoring.@en

Angiogenesis is a critical feature of plaque development in atherosclerosis and might play a key role in both the initiation and later rupture of plaques. The precursory molecular or cellular pro-angiogenic events that initiate plaque growth and that ultimately contribute to plaque instability, however, cannot be detected directly with any current diagnostic modality. This study was designed to investigate the feasibility of ultrasound molecular imaging of endothelial αvβ3 expression in vitro and in vivo using αvβ3-targeted ultrasound contrast agents (UCAs). In the in vitro study, αvβ3 expression was confirmed by immunofluorescence in a murine endothelial cell line and detected using the targeted UCA and ultrasound imaging at 18-MHz transmit frequency. In the in vivo study, expression of endothelial αvβ3 integrin in murine carotid artery vessels and microvessels of the salivary gland was quantified using targeted UCA and high-frequency ultrasound in seven animals. Our results indicated that endothelial αvβ3 expression was significantly higher in the carotid arterial wall containing atherosclerotic lesions than in arterial segments without any lesions. We also found that the salivary gland can be used as an internal positive control for successful binding of targeted UCA to αvβ3 integrin. In conclusion, αvβ3-targeted UCA allows non-invasive assessment of the expression levels of αvβ3 on the vascular endothelium and may provide potential insights into early atherosclerotic plaque detection and treatment monitoring.@en

Angiogenesis is a critical feature of plaque development in atherosclerosis and might play a key role in both the initiation and later rupture of plaques. The precursory molecular or cellular pro-angiogenic events that initiate plaque growth and that ultimately contribute to plaque instability, however, cannot be detected directly with any current diagnostic modality. This study was designed to investigate the feasibility of ultrasound molecular imaging of endothelial αvβ3 expression in vitro and in vivo using αvβ3-targeted ultrasound contrast agents (UCAs). In the in vitro study, αvβ3 expression was confirmed by immunofluorescence in a murine endothelial cell line and detected using the targeted UCA and ultrasound imaging at 18-MHz transmit frequency. In the in vivo study, expression of endothelial αvβ3 integrin in murine carotid artery vessels and microvessels of the salivary gland was quantified using targeted UCA and high-frequency ultrasound in seven animals. Our results indicated that endothelial αvβ3 expression was significantly higher in the carotid arterial wall containing atherosclerotic lesions than in arterial segments without any lesions. We also found that the salivary gland can be used as an internal positive control for successful binding of targeted UCA to αvβ3 integrin. In conclusion, αvβ3-targeted UCA allows non-invasive assessment of the expression levels of αvβ3 on the vascular endothelium and may provide potential insights into early atherosclerotic plaque detection and treatment monitoring.@en

High-frame-rate (HFR) echo-particle image velocimetry (echoPIV) is a promising tool for measuring intracardiac blood flow dynamics. In this study, we investigate the optimal ultrasound contrast agent (UCA: SonoVue) infusion rate and acoustic output to use for HFR echoPIV (PRF = 4900 Hz) in the left ventricle (LV) of patients. Three infusion rates (0.3, 0.6, and 1.2 ml/min) and five acoustic output amplitudes (by varying transmit voltage: 5, 10, 15, 20, and 30 V - corresponding to mechanical indices of 0.01, 0.02, 0.03, 0.04, and 0.06 at 60-mm depth) were tested in 20 patients admitted for symptoms of heart failure. We assess the accuracy of HFR echoPIV against pulsed-wave Doppler acquisitions obtained for mitral inflow and aortic outflow. In terms of image quality, the 1.2-ml/min infusion rate provided the highest contrast-to-background ratio (CBR) (3-dB improvement over 0.3 ml/min). The highest acoustic output tested resulted in the lowest CBR. Increased acoustic output also resulted in increased microbubble disruption. For the echoPIV results, the 1.2-ml/min infusion rate provided the best vector quality and accuracy; mid-range acoustic outputs (corresponding to 15-20-V transmit voltages) provided the best agreement with the pulsed-wave Doppler. Overall, the highest infusion rate (1.2 ml/min) and mid-range acoustic output amplitudes provided the best image quality and echoPIV results.@en

Over the past decades, real-time three-dimensional (3D) medical ultrasound has attracted much attention since it enables clinicians to diagnose more accurately. This calls for ultrasound matrix transducers with a large number of elements, which can be interfaced with an application-specific integrated circuit (ASIC) for data reduction. An important aspect of the design of such a transducer is the geometry of each element, since it affects the mode of vibration and, consequently, the efficiency of the transducer. In this paper, we experimentally investigate the effect of subdicing on a piezoelectric (PZT) transducer. We fabricate and acoustically characterize a prototype PZT matrix transducer built on top of ASICs. The prototype transducer contains subdiced and non-subdiced elements, whose performance can be directly compared under the same conditions. Measurement results show that subdiced elements have a better performance compared to non-subdiced ones. Subdicing increases the peak pressure by 25%, raises the bandwidth by 10% and reduces the ringing time by 25%.@en

Over the past decades, ultrasound imaging has made considerable progress based on the advancement of imaging systems as well as transducer technology. With the need for advanced transducer arrays with complex designs and technical requirements, there is also a need for suitable tools to characterize such transducers. However, despite the importance of acoustic characterization to assess the performance of novel transducer arrays, the characterization process of highly complex transducers might involve various manual steps, which are laborious, time-consuming, and subject to errors. These factors can hinder the full characterization of a prototype transducer, leading to an under-representation or inadequate evaluation. To come to an extensive, high-quality evaluation of a prototype transducer, the acoustic characterization of each transducer element is indispensable in both transmit and receive operations. In this paper, we propose a pipeline to automatically perform the acoustic characterization of a matrix transducer using a research imaging system. The performance of the pipeline is tested on a prototype matrix transducer consisting of 960 elements. The results show that the proposed pipeline is capable of performing the complete acoustic characterization of a high-element count transducer in a fast and convenient way. @en

Purpose: Intraventricular blood flow dynamics are associated with cardiac function. Accurate, noninvasive, and easy assessments of hemodynamic quantities (such as velocity, vortex, and pressure) could be an important addition to the clinical diagnosis and treatment of heart diseases. However, the complex time-varying flow brings many challenges to the existing noninvasive image-based hemodynamic assessments. The development of reliable techniques and analysis tools is essential for the application of hemodynamic biomarkers in clinical practice. Methods: In this study, a time-resolved particle tracking method, Shake-the-Box, was applied to reconstruct the flow in a realistic left ventricle (LV) silicone model with biological valves. Based on the obtained velocity, 4D pressure field was calculated using a Poisson equation-based pressure solver. Furthermore, flow analysis by proper orthogonal decomposition (POD) of the 4D velocity field has been performed. Results: As a result of the Shake-the-Box algorithm, we have extracted: (i) particle positions, (ii) particle tracks, and finally, (iii) 4D velocity fields. From the latter, the temporal evolution of the 3D pressure field during the full cardiac cycle was obtained. The obtained maximal pressure difference extracted along the base-to-apex was about 2.7 mmHg, which is in good agreement with those reported in vivo. The POD analysis results showed a clear picture of different scale of vortices in the pulsatile LV flow, together with their time-varying information and corresponding kinetic energy content. To reconstruct 95% of the kinetic energy of the LV flow, only the first six POD modes would be required, leading to significant data reduction. Conclusions: This work demonstrated Shake-the-Box is a promising technique to accurately reconstruct the left ventricle flow field in vitro. The good spatial and temporal resolutions of the velocity measurements enabled a 4D reconstruction of the pressure field in the left ventricle. The application of POD analysis showed its potential in reducing the complexity of the high-resolution left ventricle flow measurements. For future work, image analysis, multi-modality flow assessments, and the development of new flow-derived biomarkers can benefit from fast and data-reducing POD analysis.@en

Intravascular ultrasound (IVUS) is a well-established diagnostic method that provides images of the vessel wall and atherosclerotic plaques. We investigate the potential for phased-array IVUS utilizing coded excitation (CE) for improving the penetration depth and image signal-to-noise ratio (SNR). It is realized on a new experimental broadband capacitive micromachined ultrasound transducer (CMUT) array, operated in collapse mode, with 96 elements placed at the circumference of a catheter tip with a 1.2- {mm} diameter. We characterized the array performance for CE imaging and showed that the -6-dB device bandwidth at a 30-V dc biasing is 25 MHz with a 20-MHz center frequency, with a transmit sensitivity of 37 kPa/V at that frequency. We designed a linear frequency modulation code to improve penetration depth by compensating for high-frequency attenuation while preserving resolution by a mismatched filter reconstruction. We imaged a wire phantom and a human coronary artery plaque. By assessing the image quality of the reconstructed wire phantom image, we achieved 60- and 70- mu{mathrm {m}} axial resolutions using the short pulse and coded signal, respectively, and gained 8 dB in SNR for CE. Our developed system shows 20-frames/s, pixel-based beam-formed, real-time IVUS images.@en

Recently, we realized a prototype matrix transducer consisting of 48 rows of 80 elements on top of a tiled set of Application Specific Integrated Circuits (ASICs) implementing a row-level control connecting one transmit/receive channel to an arbitrary subset of elements per row. A fully sampled array data acquisition is implemented by a column-by-column (CBC) imaging scheme (80 transmit-receive shots) which achieves 250 volumes/second (V/s) at a pulse repetition frequency of 20 kHz. However, for several clinical applications such as carotid pulse wave imaging (CPWI), a volume rate of 1000 per second is needed. This allows only 20 transmit-receive shots per 3D image. In this study, we propose a shifting aperture scheme and investigate the effects of receive/transmit aperture size and aperture shifting step in the elevation direction. The row-level circuit is used to interconnect elements of a receive aperture in the elevation (row) direction. An angular weighting method is used to suppress the grating lobes caused by the enlargement of the effective elevation pitch of the array, as a result of element interconnection in the elevation direction. The effective aperture size, level of grating lobes, and resolution/sidelobes are used to select suitable reception/transmission parameters. Based on our assessment, the proposed imaging sequence is a full transmission (all 80 elements excited at the same time), a receive aperture size of 5 and an aperture shifting step of 3. Numerical results obtained at depths of 10, 15, and 20 mm show that, compared to the fully sampled array, the 1000 V/s is achieved at the expense of, on average, about two times wider point spread function and 4 dB higher clutter level. The resulting grating lobes were at -27 dB. The proposed imaging sequence can be used for carotid pulse wave imaging to generate an informative 3D arterial stiffness map, for cardiovascular disease assessment.@en

This article presents a compact analog front-end (AFE) circuit for ultrasound receivers with linear-in-dB continuous gain control for time-gain compensation (TGC). The AFE consists of two variable-gain stages, both of which employ a novel complementary current-steering network (CCSN) as the interpolator to realize continuously variable gain. The first stage is a trans-impedance amplifier (TIA) with a hardware-sharing inverter-based input stage to save power and area. The TIA's output couples capacitively to the second stage, which is a class-AB current amplifier (CA). The AFE is integrated into an application-specific integrated circuit (ASIC) in a 180-nm high-voltage BCD technology and assembled with a 100 μm-pitch PZT transducer array of 8 × 8 elements. Both electrical and acoustic measurements show that the AFE achieves a linear-in-dB gain error below ±0.4 dB within a 36-dB gain range, which is > 2 × better than the prior art. Per channel, the AFE occupies 0.025 mm2 area, consumes 0.8 mW power, and achieves an input-referred noise density of 1.31 pA/√Hz.@en

Left ventricular (LV) blood flow is an inherently complex time-varying 3-D phenomenon, where 2-D quantification often ignores the effect of out-of-plane motion. In this study, we describe high frame rate 4-D echocardiographic particle image velocimetry (echo-PIV) using a prototype matrix transesophageal transducer and a dynamic LV phantom for testing the accuracy of echo-PIV in the presence of complex flow patterns. Optical time-resolved tomographic PIV (tomo-PIV) was used as a reference standard for comparison. Echo-PIV and tomo-PIV agreed on the general profile of the LV flow patterns, but echo-PIV smoothed out the smaller flow structures. Echo-PIV also underestimated the flow rates at greater imaging depths, where the PIV kernel size and transducer point spread function were large relative to the velocity gradients. We demonstrate that 4-D echo-PIV could be performed in just four heart cycles, which would require only a short breath-hold, providing promising results. However, methods for resolving high velocity gradients in regions of poor spatial resolution are required before clinical translation.@en

For the quantification of myocardial function, myocardial stiffness can potentially be measured non-invasively using shear wave elastography. Clinical diagnosis requires high precision. In 10 healthy volunteers, we studied the reproducibility of the measurement of propagation speeds of shear waves induced by aortic and mitral valve closure (AVC, MVC). Inter-scan was slightly higher but in similar ranges as intra-scan variability (AVC: 0.67 m/s (interquartile range [IQR]: 0.40–0.86 m/s) versus 0.38 m/s (IQR: 0.26–0.68 m/s), MVC: 0.61 m/s (IQR: 0.26–0.94 m/s) versus 0.26 m/s (IQR: 0.15–0.46 m/s)). For AVC, the propagation speeds obtained on different day were not statistically different (p = 0.13). We observed different propagation speeds between 2 systems (AVC: 3.23–4.25 m/s [Zonare ZS3] versus 1.82–4.76 m/s [Philips iE33]), p = 0.04). No statistical difference was observed between observers (AVC: p = 0.35). Our results suggest that measurement inaccuracies dominate the variabilities measured among healthy volunteers. Therefore, measurement precision can be improved by averaging over multiple heartbeats.@en

High frame rate three-dimensional (3D) ultrasound imaging would offer excellent possibilities for the accurate assessment of carotid artery diseases. This calls for a matrix transducer with a large aperture and a vast number of elements. Such a matrix transducer should be interfaced with an application-specific integrated circuit (ASIC) for channel reduction. However, the fabrication of such a transducer integrated with one very large ASIC is very challenging and expensive. In this study, we develop a prototype matrix transducer mounted on top of multiple identical ASICs in a tiled configuration. The matrix was designed to have 7680 piezoelectric elements with a pitch of 300 μm × 150 μm integrated with an array of 8 × 1 tiled ASICs. The performance of the prototype is characterized by a series of measurements. The transducer exhibits a uniform behavior with the majority of the elements working within the −6 dB sensitivity range. In transmit, the individual elements show a center frequency of 7.5 MHz, a −6 dB bandwidth of 45%, and a transmit efficiency of 30 Pa/V at 200 mm. In receive, the dynamic range is 81 dB, and the minimum detectable pressure is 60 Pa per element. To demonstrate the imaging capabilities, we acquired 3D images using a commercial wire phantom.@en

In this letter, a compact high-voltage (HV) transmit circuit for dense 2-D transducer arrays used in 3-D ultrasonic imaging systems is presented. Stringent area requirements are addressed by a unipolar pulser with embedded transmit/receive switch. Combined with a capacitive HV level shifter, it forms the ultrasonic HV transmit circuit with the lowest reported HV transistor count and area without any static power consumption. The balanced latched-based level shifter implementation makes the design insensitive to transients on the HV supply caused by pulsing, facilitating application in probes with limited local supply decoupling, such as imaging catheters. Favorable scaling through resource sharing benefits massively arrayed architectures while preserving full individual functionality. A prototype of 8 × 9 elements was fabricated in the TSMC 0.18 μm HV BCD technology and a 160μm×160μm PZT transducer matrix is manufactured on the chip. The system is designed to drive 65-V peak-to-peak pulses on 2-pF transducer capacitance and hardware sharing of six elements allows for an area of only 0.008 mm2 per element. Electrical characterization as well as acoustic results obtained with the 6-MHz central frequency transducer are demonstrated.@en

The propagation velocity of shear waves relates to tissue stiffness. We prove that a regular clinical cardiac ultrasound system can determine shear wave velocity with a conventional unmodified tissue Doppler imaging (TDI) application. The investigation was performed on five tissue phantoms with different stiffness using a research platform capable of inducing and tracking shear waves and a clinical cardiac system (Philips iE33, achieving frame rates of 400–700 Hz in TDI by tuning the normal system settings). We also tested the technique in vivo on a normal individual and on typical pathologies modifying the consistency of the left ventricular wall. The research platform scanner was used as reference. Shear wave velocities measured with TDI on the clinical cardiac system were very close to those measured by the research platform scanner. The mean difference between the clinical and research systems was 0.18 ± 0.22 m/s, and the limits of agreement, from −0.27 to +0.63 m/s. In vivo, the velocity of the wave induced by aortic valve closure in the interventricular septum increased in patients with expected increased wall stiffness.@en