Ultrasonic Sound Speed Estimation for Liver Fat Quantification: A Review by the AIUM-RSNA QIBA Pulse-Echo Quantitative Ultrasound Initiative.

Non-alcoholic fatty liver disease (NAFLD) is a significant cause of diffuse liver disease, morbidity and mortality worldwide. Early and accurate diagnosis of NALFD is critical to identify patients at risk of disease progression. Liver biopsy is the current gold standard for diagnosis and prognosis. However, a non-invasive diagnostic tool is desired because of the high cost and risk of complications of tissue sampling. Medical ultrasound is a safe, inexpensive and widely available imaging tool for diagnosing NAFLD. Emerging sonographic tools to quantitatively estimate hepatic fat fraction, such as tissue sound speed estimation, are likely to improve diagnostic accuracy, precision and reproducibility compared with existing qualitative and semi-quantitative techniques. Various pulse-echo ultrasound speed of sound estimation methodologies have been investigated, and some have been recently commercialized. We review state-of-the-art in vivo speed of sound estimation techniques, including their advantages, limitations, technical sources of variability, biological confounders and existing commercial implementations. We report the expected range of hepatic speed of sound as a function of liver steatosis and fibrosis that may be encountered in clinical practice. Ongoing efforts seek to quantify sound speed measurement accuracy and precision to inform threshold development around meaningful differences in fat fraction and between sequential measurements.

Quantitative Hepatic Fat Quantification in Non-alcoholic Fatty Liver Disease Using Ultrasound-Based Techniques: A Review of Literature and Their Diagnostic Performance.

Non-alcoholic fatty liver disease is a condition that is characterized by the presence of >5% fat in the liver and affects more than one billion people worldwide. If adequate and early precautions are not taken, non-alcoholic fatty liver disease can progress to cirrhosis and death. The current reference standard for detecting hepatic steatosis is a liver biopsy. However, because of the potential morbidity associated with liver biopsies, non-invasive imaging biomarkers have been extensively investigated. Magnetic resonance imaging-based methods have proven accuracy in quantifying liver steatosis; however, these techniques are costly and have limited availability. Ultrasound-based quantitative imaging techniques are increasingly utilized because of their widespread availability, ease of use and relative cost-effectiveness. Several ultrasound-based liver fat quantification techniques have been investigated, including techniques that measure changes in the acoustic properties of the liver caused by the presence of fat. In this review, we focus on quantitative ultrasound approaches and their diagnostic performance in the realm of non-alcoholic fatty liver disease.

Surgery for Obesity and Related Diseases: I. A Novel Approach to the Quantification of the Longitudinal Speed of Sound and Its Potential for Tissue Characterization.

Described here is a method to determine the longitudinal speed of sound in speckle-dominated ultrasound images. The method is based on the concept that the quality of an ultrasound image is maximized when the beamformer's speed of sound matches the speed in the medium. The method captures the quality of the ultrasound image using two quantitative image-quality metrics: image brightness and sharpness around the intended focal zone. The proposed method requires no calibration, is computationally efficient and is deployable on commercial ultrasound systems without hardware or software modifications. Ex vivo testing on tissue-mimicking phantoms indicates the method's accuracy in predicting the true speed of sound to within 1% of ground truth values.

Experimental Validation of Longitudinal Speed of Sound Estimates in the Diagnosis of Hepatic Steatosis (Part II).

This study validates a non-invasive, quantitative technique to diagnose steatosis within tissue. The proposed method is based on two fundamental concepts: (i) the speed of sound in a fatty liver is lower than that in a healthy liver and (ii) the quality of an ultrasound image is maximized when the beamformer's speed of sound matches the speed in the medium under examination. The method uses image brightness and sharpness as quantitative image-quality metrics to predict the true sound speed and capture the effects of fat infiltration, while accounting for the transmission through subcutaneous fat. Ex vivo testing on sheep liver, mouse livers and tissue-mimicking phantoms indicated the technique's ability to predict the true speed of sound with errors less than 0.5% and to quantify the inverse correlation between fat content and speed of sound.

A Column-Row-Parallel Ultrasound Imaging Architecture for 3-D Plane-Wave Imaging and Tx Second-Order Harmonic Distortion Reduction.

We propose a column-row-parallel imaging front-end architecture for integrated and low-power 3-D medical ultrasound imaging. The column-row-parallel architecture offers linear-scaling interconnection, acquisition, and programming time with row-by-row or column-by-column operations, while supporting volumetric imaging functionality and fault-tolerance against possible transducer element defects with per-element controls. The combination of column-parallel selection logic, row-parallel selection logic, and per-element selection logic reaches a balance between flexible imaging aperture definition and manageable imaging data/control interface to a 2-D array. A capacitive micromachined ultrasonic transducer (CMUT)-application-specific integrated circuit (ASIC) column-row-parallel prototype is fabricated and assembled with a flip-chip bonding process. It facilitates the 3-D plane-wave coherent compounding algorithm for volumetric imaging with a fast frame rate of 62.5 Hz and 46% improved lateral resolution with 10-angle compounding and a field of view volume of 2.3 mm in both azimuth and elevation, 8.5 mm in depth. At a hypothetically scaled up array size, the frame rate can still be kept at 31.2 Hz for a volume of 40 mm in both azimuth and elevation, 150 mm in depth. An interleaved checkerboard pattern with in-phase ( ) and quadrature ( ) excitations is also demonstrated for reducing CMUT second-harmonic distortion emission by up to 25 dB at the loss of 3-dB fundamental energy reduction. The method reduces nonlinear effects from both transducers and circuits and is a wide band technique that is applicable to arbitrary pulse shapes.

Quantitative analysis of vascular heterogeneity in breast lesions using contrast-enhanced 3-D harmonic and subharmonic ultrasound imaging.

Ability to visualize breast lesion vascularity and quantify the vascular heterogeneity using contrast-enhanced 3-D harmonic (HI) and subharmonic (SHI) ultrasound imaging was investigated in a clinical population. Patients (n = 134) identified with breast lesions on mammography were scanned using power Doppler imaging, contrast-enhanced 3-D HI, and 3-D SHI on a modified Logiq 9 scanner (GE Healthcare). A region of interest corresponding to ultrasound contrast agent flow was identified in 4D View (GE Medical Systems) and mapped to raw slice data to generate a map of time-intensity curves for the lesion volume. Time points corresponding to baseline, peak intensity, and washout of ultrasound contrast agent were identified and used to generate and compare vascular heterogeneity plots for malignant and benign lesions. Vascularity was observed with power Doppler imaging in 84 lesions (63 benign and 21 malignant). The 3-D HI showed flow in 8 lesions (5 benign and 3 malignant), whereas 3-D SHI visualized flow in 68 lesions (49 benign and 19 malignant). Analysis of vascular heterogeneity in the 3-D SHI volumes found benign lesions having a significant difference in vascularity between central and peripheral sections (1.71 ± 0.96 vs. 1.13 ± 0.79 dB, p < 0.001, respectively), whereas malignant lesions showed no difference (1.66 ± 1.39 vs. 1.24 ± 1.14 dB, p = 0.24), indicative of more vascular coverage. These preliminary results suggest quantitative evaluation of vascular heterogeneity in breast lesions using contrast-enhanced 3-D SHI is feasible and able to detect variations in vascularity between central and peripheral sections for benign and malignant lesions.

Therapeutic ultrasound: Increased HDL-Cholesterol following infusions of acoustic microspheres and apolipoprotein A-I plasmids.

BACKGROUND: Low levels of HDL-C are an independent cardiovascular risk factor associated with increased premature cardiovascular death. However, HDL-C therapies historically have been limited by issues relating to immunogenicity, hepatotoxicity and scalability, and have been ineffective in clinical trials. OBJECTIVE: We examined the feasibility of using injectable acoustic microspheres to locally deliver human ApoA-I DNA plasmids in a pre-clinical model and quantify increased production of HDL-C in vivo. METHODS: Our novel site-specific gene delivery system was examined in naïve rat model and comprised the following steps: (1) intravenous co-administration of a solution containing acoustically active microspheres (Optison™, GE Healthcare, Princeton, New Jersey) and human ApoA-I plasmids; (2) ultrasound verification of the presence of the microspheres within the liver vasculature; (3) External application of locally-directed acoustic energy, (4) induction of microsphere disruption and in situ sonoporation; (4) ApoA-I plasmid hepatic uptake; (5) transcription and expression of human ApoA-I protein; and (6) elevation of serum HDL-C. RESULTS: Co-administration of ApoA-I plasmids and acoustic microspheres, activated by external ultrasound energy, resulted in transcription and production of human ApoA-I protein and elevated serum HDL-C in rats (up to 61%; p-value < 0.05). CONCLUSIONS: HDL-C was increased in rats following ultrasound directed delivery of human ApoA-I plasmids by microsphere sonoporation. The present method provides a novel approach to promote ApoA-I synthesis and nascent HDL-C elevation, potentially permitting the use of a minimally-invasive ultrasound-based, gene delivery system for treating individuals with low HDL-C.

Reconfigurable mosaic annular arrays.

Mosaic annular arrays (MAA) based on reconfigurable array (RA) transducer electronics assemblies are presented as a potential solution for future highly integrated ultrasonic transducer subsystems. Advantages of MAAs include excellent beam quality and depth of field resulting from superior elevational focus compared with 1-D electronically scanned arrays, as well as potentially reduced cost, size, and power consumption resulting from the use of a limited number of beamforming channels for processing a large number of subelements. Specific design tradeoffs for these highly integrated arrays are discussed in terms of array specifications for center frequency, element pitch, and electronic switch-on resistance. Large-area RAs essentially function as RC delay lines. Efficient architectures which take into account RC delay effects are presented. Architectures for integration of the transducer and electronics layers of large-area array implementations are reviewed.

Perfusion estimation using contrast-enhanced 3-dimensional subharmonic ultrasound imaging: an in vivo study.

OBJECTIVES: The ability to estimate tissue perfusion (in milliliter per minute per gram) in vivo using contrast-enhanced 3-dimensional (3D) harmonic and subharmonic ultrasound imaging was investigated. MATERIALS AND METHODS: A LOGIQ™ 9 scanner (GE Healthcare, Milwaukee, WI) equipped with a 4D10L probe was modified to perform 3D harmonic imaging (HI; f(transmit), 5 MHz and f(receive), 10 MHz) and subharmonic imaging (SHI; f(transmit), 5.8 MHz and f(receive), 2.9 MHz). In vivo imaging was performed in the lower pole of both kidneys in 5 open-abdomen canines after injection of the ultrasound contrast agent (UCA) Definity (Lantheus Medical Imaging, N Billerica, MA). The canines received a 5-µL/kg bolus injection of Definity for HI and a 20-µL/kg bolus for SHI in triplicate for each kidney. Ultrasound data acquisition was started just before the injection of UCA (to capture the wash-in) and continued until washout. A microvascular staining technique based on stable (nonradioactive) isotope-labeled microspheres (Biophysics Assay Laboratory, Inc, Worcester, MA) was used to quantify the degree of perfusion in each kidney (the reference standard). Ligating a surgically exposed branch of the renal arteries induced lower perfusion rates. This was followed by additional contrast-enhanced imaging and microsphere injections to measure post-ligation perfusion. Slice data were extracted from the 3D ultrasound volumes and used to generate time-intensity curves offline in the regions corresponding to the tissue samples used for microvascular staining. The midline plane was also selected from the 3D volume (as a quasi-2-dimensional [2D] image) and compared with the 3D imaging modes. Perfusion was estimated from the initial slope of the fractional blood volume uptake (for both HI and SHI) and compared with the reference standard using linear regression analysis. RESULTS: Both 3D HI and SHI were able to provide visualization of flow and, thus, perfusion in the kidneys. However, SHI provided near-complete tissue suppression and improved visualization of the UCA flow. Microsphere perfusion data were available for 4 canines (1 was excluded because of an error with the reference blood sample) and showed a mean (SD) perfusion of 9.30 (6.60) and 5.15 (3.42) mL/min per gram before and after the ligation, respectively. The reference standard showed significant correlation with the overall 3D HI perfusion estimates (r = 0.38; P = 0.007), but it correlated more strongly with 3D SHI (r = 0.62; P < 0.001). In addition, these results showed an improvement over the quasi-2D HI and SHI perfusion estimates (r = -0.05 and r = 0.14) and 2D SHI perfusion estimates previously reported by our group (r = 0.57). CONCLUSIONS: In this preliminary study, 3D contrast-enhanced nonlinear ultrasound was able to quantify perfusion in vivo. Three-dimensional SHI resulted in better overall agreement with the reference standard than 3D HI did and was superior to previously reported 2D SHI results. Three-dimensional SHI outperforms the other methods for estimating blood perfusion because of the improved visualization of the complete perfused vascular networks.

A beamforming study for implementation of vibro-acoustography with a 1.75-D array transducer.

Vibro-acoustography (VA) is an ultrasound-based imaging modality that uses radiation force produced by two cofocused ultrasound beams separated by a small frequency difference, Δf, to vibrate tissue at Δf. An acoustic field is created by the object vibration and measured with a nearby hydrophone. This method has recently been implemented on a clinical ultrasound system using 1-D linear-array transducers. In this article, we discuss VA beamforming and image formation using a 1.75-D array transducer. A 1.75-D array transducer has several rows of elements in the elevation direction which can be controlled independently for focusing. The advantage of the 1.75-D array over a 1-D linear-array transducer is that multiple rows of elements can be used for improving elevation focus for imaging formation. Six configurations for subaperture design for the two ultrasound beams necessary for VA imaging were analyzed. The point-spread functions for these different configurations were evaluated using a numerical simulation model. Four of these configurations were then chosen for experimental evaluation with a needle hydrophone as well as for scanning two phantoms. Images were formed by scanning a urethane breast phantom and an ex vivo human prostate. VA imaging using a 1.75-D array transducer offers several advantages over scanning with a linear-array transducer, including improved image resolution and contrast resulting from better elevation focusing of the imaging point-spread function.

Chronic liver disease: noninvasive subharmonic aided pressure estimation of hepatic venous pressure gradient.

PURPOSE: To compare subharmonic aided pressure estimation (SHAPE) with pressure catheter-based measurements in human patients with chronic liver disease undergoing transjugular liver biopsy. MATERIALS AND METHODS: This HIPAA-compliant study had U.S. Food and Drug Administration and institutional review board approval, and written informed consent was obtained from all participants. Forty-five patients completed this study between December 2010 and December 2011. A clinical ultrasonography (US) scanner was modified to obtain SHAPE data. After transjugular liver biopsy with pressure measurements as part of the standard of care, 45 patients received an infusion of a microbubble US contrast agent and saline. During infusion, SHAPE data were collected from a portal and hepatic vein and were compared with invasive measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student t test. RESULTS: The 45 study patients included 27 men and 18 women (age range, 19-71 years; average age, 55.8 years). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the hepatic venous pressure gradient (HVPG) (R = 0.82). Patients at increased risk for variceal hemorrhage (HVPG ≥ 12 mm Hg) had a significantly higher mean subharmonic gradient than patients with lower HVPGs (1.93 dB ± 0.61 [standard deviation] vs -1.47 dB ± 0.29, P < .001), with a sensitivity of 100% and a specificity of 81%, indicating that SHAPE may be a useful tool for the diagnosis of clinically important portal hypertension. CONCLUSION: Preliminary results show SHAPE to be an accurate noninvasive technique for estimating portal hypertension.

Packaging and modular assembly of large-area and fine-pitch 2-D ultrasonic transducer arrays.

A promising transducer architecture for largearea arrays employs 2-D capacitive micromachined ultrasound transducer (CMUT) devices with backside trench-frame pillar interconnects. Reconfigurable array (RA) application-specified integrated circuits (ASICs) can provide efficient interfacing between these high-element-count transducer arrays and standard ultrasound systems. Standard electronic assembly techniques such as flip-chip and ball grid array (BGA) attachment, along with organic laminate substrate carriers, can be leveraged to create large-area arrays composed of tiled modules of CMUT chips and interface ASICs. A large-scale, fully populated and integrated 2-D CMUT array with 32 by 192 elements was developed and demonstrates the feasibility of these techniques to yield future large-area arrays. This study demonstrates a flexible and reliable integration approach by successfully combining a simple under-bump metallization (UBM) process and a stacked CMUT/interposer/ASIC module architecture. The results show high shear strength of the UBM (26.5 g for 70-µm balls), high interconnect yield, and excellent CMUT resonance uniformity (s = 0.02 MHz). A multi-row linear array was constructed using the new CMUT/interposer/ASIC process using acoustically active trench-frame CMUT devices and mechanical/ nonfunctional Si backside ASICs. Imaging results with the completed probe assembly demonstrate a functioning device based on the modular assembly architecture.

Investigating the efficacy of subharmonic aided pressure estimation for portal vein pressures and portal hypertension monitoring.

The efficacy of using subharmonic emissions from Sonazoid microbubbles (GE Healthcare, Oslo, Norway) to track portal vein pressures and pressure changes was investigated in 14 canines using either slow- or high-flow models of portal hypertension (PH). A modified Logiq 9 scanner (GE Healthcare, Milwaukee, WI, USA) operating in subharmonic mode (f(transmit): 2.5 MHz, f(receive): 1.25 MHz) was used to collect radiofrequency data at 10-40% incident acoustic power levels with 2-4 transmit cycles (in triplicate) before and after inducing PH. A pressure catheter (Millar Instruments, Inc., Houston, TX, USA) provided reference portal vein pressures. At optimum insonification, subharmonic signal amplitude changes correlated with portal vein pressure changes; r ranged from -0.82 to -0.94 and from -0.70 to -0.73 for PH models considered separately or together, respectively. The subharmonic signal amplitudes correlated with absolute portal vein pressures (r: -0.71 to -0.79). Statistically significant differences between subharmonic amplitudes, before and after inducing PH, were noted (p ≤ 0.01). Portal vein pressures estimated using subharmonic aided pressure estimation did not reveal significant differences (p > 0.05) with respect to the pressures obtained using the Millar pressure catheter. Subharmonic-aided pressure estimation may be useful clinically for portal vein pressure monitoring.

Three-dimensional subharmonic ultrasound imaging in vitro and in vivo.

RATIONALE AND OBJECTIVES: Although contrast-enhanced ultrasound imaging techniques such as harmonic imaging (HI) have evolved to reduce tissue signals using the nonlinear properties of the contrast agent, levels of background suppression have been mixed. Subharmonic imaging (SHI) offers near complete tissue suppression by centering the receive bandwidth at half the transmitting frequency. The aims of this study were to demonstrate the feasibility of three-dimensional (3D) SHI and to compare it to 3D HI. MATERIALS AND METHODS: Three-dimensional HI and SHI were implemented on a Logiq 9 ultrasound scanner with a 4D10L probe. Four-cycle SHI was implemented to transmit at 5.8 MHz and receive at 2.9 MHz, while two-cycle HI was implemented to transmit at 5 MHz and receive at 10 MHz. The ultrasound contrast agent Definity was imaged within a flow phantom and the lower pole of two canine kidneys in both HI and SHI modes. Contrast-to-tissue ratios and rendered images were compared offline. RESULTS: SHI resulted in significant improvement in contrast-to-tissue ratios relative to HI both in vitro (12.11 ± 0.52 vs 2.67 ± 0.77, P< .001) and in vivo (5.74 ± 1.92 vs 2.40 ± 0.48, P = .04). Rendered 3D subharmonic images provided better tissue suppression and a greater overall view of vessels in a flow phantom and canine renal vasculature. CONCLUSIONS: The successful implementation of SHI in 3D allows imaging of vascular networks over a heterogeneous sample volume and should improve future diagnostic accuracy. Additionally, 3D SHI provides improved contrast-to-tissue ratios relative to 3D HI.

The feasibility of using thermal strain imaging to regulate energy delivery during intracardiac radio-frequency ablation.

A method is introduced to monitor cardiac ablative therapy by examining slope changes in the thermal strain curve caused by speed of sound variations with temperature. The sound speed of water-bearing tissue such as cardiac muscle increases with temperature. However, at temperatures above about 50°C, there is no further increase in the sound speed and the temperature coefficient may become slightly negative. For ablation therapy, an irreversible injury to tissue and a complete heart block occurs in the range of 48 to 50°C for a short period in accordance with the well-known Arrhenius equation. Using these two properties, we propose a potential tool to detect the moment when tissue damage occurs by using the reduced slope in the thermal strain curve as a function of heating time. We have illustrated the feasibility of this method initially using porcine myocardium in vitro. The method was further demonstrated in vivo, using a specially equipped ablation tip and an 11-MHz microlinear intracardiac echocardiography (ICE) array mounted on the tip of a catheter. The thermal strain curves showed a plateau, strongly suggesting that the temperature reached at least 50°C.

Implementation of vibro-acoustography on a clinical ultrasound system.

Vibro-acoustography is an ultrasound-based imaging modality that uses two ultrasound beams of slightly different frequencies to produce images based on the acoustic response caused by harmonic ultrasound radiation force excitation at the difference frequency between the two ultrasound frequencies. Vibro-acoustography has demonstrated feasibility and usefulness in imaging of breast and prostate tissue. However, previous studies have been performed either in controlled water tank settings or a prototype breast scanner equipped with a water tank. To make vibro-acoustography more accessible and relevant to clinical use, we report here on the implementation of vibro-acoustography on a General Electric Vivid 7 ultrasound scanner. In this paper, we will describe software and hardware modifications that were performed to make vibro- acoustography functional on this system. We will discuss aperture definition for the two ultrasound beams and beamforming using a linear-array transducer. Experimental results from beam measurements and phantom imaging studies will be shown. The implementation of vibro-acoustography provides a step toward clinical translation of this imaging modality for applications in various organs including breast, prostate, thyroid, kidney, and liver.

The thermal index: its strengths, weaknesses, and proposed improvements.

The thermal index (TI) has been used as a relative indicator of thermal risk during diagnostic ultrasound examinations for many years. It is useful in providing feedback to the clinician or sonographer, allowing assessment of relative, potential risks to the patient of an adverse effect due to a thermal mechanism. Recently, several shortcomings of the TI formulations in quantifying the risk to the patient have been identified by members of the basic scientific community, and possible improvements to address these shortcomings have been proposed. For this reason, the Output Standards Subcommittee of the American Institute of Ultrasound in Medicine convened a subcommittee to review the strengths of the TI formulations as well as their weaknesses and proposed improvements. This article summarizes the findings of this subcommittee. After a careful review of the literature and an assessment of the cost of updating the TI formulations while maximizing the quality of patient care, the Output Standards Subcommittee makes the following recommendations: (1) some inconsistencies in the current TI formulations should be resolved, and the break point distance should be redefined to take focusing into consideration; (2) an entirely new indicator of thermal risk that incorporates the time dependence not be implemented at this time but be included in continuing efforts toward standards or consensus documents; (3) the exponential dependence of risk on temperature not be incorporated into a new definition of the TI formulations at this time but be included in continuing efforts toward standards or consensus documents; (4) the TI formulations not be altered to include nonlinear propagation at this time but be included in continuing efforts toward standards or consensus documents; and (5) a new indicator for risk from thermal mechanisms should be developed, distinct from the traditional TI formulations, for new imaging modalities such as acoustic radiation force impulse imaging, which have more complicated pulsing sequences than traditional imaging.

Effect of a gel retainment dam on automated ultrasound coverage in a dual-modality breast imaging system.

OBJECTIVE: The goal of this work was to evaluate a possible improvement in ultrasound coverage for a dual-modality breast imaging system in the mammographic geometry. METHODS: A pilot study was performed to evaluate use of a rubber dam to retain ultrasound gel and improve imaging coverage at the breast periphery on a combined imaging system consisting of an ultrasound scanner and a digital x-ray tomosynthesis unit. Several dams were constructed to encompass the shapes of various sizes of compressed breasts. Visual tracings of the breast-to-paddle contact area and breast periphery were made for 8 breasts to estimate coverage area. Two readers independently reviewed the resulting images and were asked to rate the overall breast image quality. RESULTS: The percentages of breast in contact with the paddle were greater (P < .01) and the linear dimensions of breast in contact with the paddle were larger (P < .05) with the rubber dam than without it. With the dam, the mean estimated area of the breast in contact with the paddle increased 14%, whereas the mean increase in the fraction of the total breast area in contact with paddle was 30%. The difference was due to the mean total projected area of the breast decreasing 12% as the dam was pressed against it. The image quality of automated ultrasound with the rubber dam was consistently judged to be superior to that without the dam. CONCLUSIONS: This method can enhance the absolute and percentage area of the breast in contact with the paddle, reducing noncontact gaps at the breast periphery. Gently pressing the breast periphery with the dam inserted toward the chest wall improves coverage in automated breast ultrasound scanning.

Contrast-enhanced ultrasound imaging of the vasa vasorum: from early atherosclerosis to the identification of unstable plaques.

Proliferation of the adventitial vasa vasorum (VV) is inherently linked with early atherosclerotic plaque development and vulnerability. Recently, direct visualization of arterial VV and intraplaque neovascularization has emerged as a new surrogate marker for the early detection of atherosclerotic disease. This clinical review focuses on contrast-enhanced ultrasound (CEUS) as a noninvasive application for identifying and quantifying carotid and coronary artery VV and intraplaque neovascularization. These novel approaches could potentially impact the clinician's ability to identify individuals with premature cardiovascular disease who are at high risk. Once clinically validated, the uses of CEUS may provide a method to noninvasively monitor therapeutic interventions. In the future, the therapeutic use of CEUS may include ultrasound-directed, site-specific therapies using microbubbles as vehicles for drug and gene delivery systems. The combined applications for diagnosis and therapy provide unique opportunities for clinicians to image and direct therapy for individuals with vulnerable lesions.