Russell H. Behler

ARFI imaging for noninvasive material characterization of atherosclerosis. Part II: toward in vivo characterization.

Seventy percent of cardiovascular disease (CVD) deaths are attributed to atherosclerosis. Despite their clinical significance, nonstenotic atherosclerotic plaques are not effectively detected by conventional atherosclerosis imaging methods. Moreover, conventional imaging methods are insufficient for describing plaque composition, which is relevant to cardiovascular risk assessment. Atherosclerosis imaging technologies capable of improving plaque detection and stratifying cardiovascular risk are needed. Acoustic radiation force impulse (ARFI) ultrasound, a novel imaging method for noninvasively differentiating the mechanical properties of tissue, is demonstrated for in vivo detection of nonstenotic plaques and plaque material assessment in this pilot investigation. In vivo ARFI imaging was performed on four iliac arteries: (1) of a normocholesterolemic pig with no atherosclerosis as a control, (2) of a familial hypercholesterolemic pig with diffuse atherosclerosis, (3) of a normocholesterolemic pig fed a high-fat diet with early atherosclerotic plaques and (4) of a familial hypercholesterolemic pig with diffuse atherosclerosis and a small, minimally occlusive plaque. ARFI results were compared with spatially matched immunohistochemistry, showing correlations between elastin and collagen content and ARFI-derived peak displacement and recovery time parameters. Faster recoveries from ARFI-induced peak displacements and smaller peak displacements were observed in areas of higher elastin and collagen content. Importantly, spatial correlations between tissue content and ARFI results were consistent and observable in large and highly evolved as well as small plaques. ARFI imaging successfully distinguished nonstenotic plaques, while conventional B-mode ultrasound did not. This work validates the potential relevance of ARFI imaging as a noninvasive imaging technology for in vivo detection and material assessment of atherosclerotic plaques.

Acoustic radiation force beam sequence performance for detection and material characterization of atherosclerotic plaques: preclinical, ex vivo results

This work presents preclinical data demonstrating performance of acoustic radiation force (ARF)-based elasticity imaging with five different beam sequences for atherosclerotic plaque detection and material characterization. Twelve trained, blinded readers evaluated parametric images taken ex vivo under simulated in vivo conditions of 22 porcine femoral arterial segments. Receiver operating characteristic (ROC) curve analysis was carried out to quantify reader performance using spatially-matched immunohistochemistry for validation. The beam sequences employed had high sensitivity (sens) and specificity (spec) for detecting Type III+ plaques (sens: 85%, spec: 79%), lipid pools (sens: 80%, spec: 86%), fibrous caps (sens: 86%, spec: 82%), calcium (sens: 96%, spec: 85%), collagen (sens: 78%, spec: 77%), and disrupted internal elastic lamina (sens: 92%, spec: 75%). 1:1 single-receive tracking yielded the highest median areas under the ROC curve (AUC), but was not statistically significantly higher than 4:1 parallel-receive tracking. Excitation focal configuration did not result in statistically different AUCs. Overall, these results suggest ARF-based imaging is relevant to detecting and characterizing plaques and support its use for diagnosing and monitoring atherosclerosis.

ARFI ultrasound for in vivo hemostasis assessment postcardiac catheterization, part II: Pilot clinical results

In this second of a two part series, we present pilot clinical data demonstrating Acoustic Radiation Force Impulse (ARFI) ultrasound for monitoring the onset of subcutaneous hemostasis at femoral artery puncture sites (arteriotomies), in vivo. We conducted a randomized, reader-blinded investigation of 20 patient volunteers who underwent diagnostic percutaneous coronary catheterization. After sheath removal (6 French), patients were randomized to treatment with either standard of care manual compression alone or, to expedite hemostasis, manual compression augmented with a p-GlcNAc fiber-based hemostatic dressing (Marine Polymer Technologies, Danvers MA). Concurrent with manual compression, serial ARFI imaging began at the time of sheath removal and continued every minute for 15 min. Serial data sets were processed with custom software to (1) estimate the time of hemostasis onset, and (2) render hybrid ARFI/B-Mode images to highlight displacements considered to correspond to extravasted blood. Images were read by an observer blinded to the treatment groups. Average estimated times to hemostasis in patient volunteers treated with manual compression alone (n = 10) and manual compression augmented by hemostatic dressing (n = 9) were, respectively, 13.00 ± 1.56 and 9.44 ± 3.09 min, which are statistically significantly different (p = 0.0065, Wilcoxon two-sample test). Example images are shown for three selected patient volunteers. These pilot data suggest that ARFI ultrasound is relevant to monitoring subcutaneous bleeding from femoral arteriotomies clinically and that time to hemostasis was significantly reduced by use of the hemostatic dressing.

ARFI Ultrasound for In Vivo Hemostasis Assessment Postcardiac Catheterization, Part I: Preclinical Studies

The world wide prevalence of cardiovascular disease leads to over seven million annual percutaneous coronary catheterization procedures, the majority of which exploit femoral artery access. Femoral puncture sites (‘arteriotomies’) can be associated with severe vessel complications after sheath removal if hemostasis is not properly achieved. Hemostasis onset is routinely determined by examination for bleeding at the skin puncture; however, clotting along the puncture path can obscure subcutaneous bleeding, and therefore hemostasis is blindly assessed. We hypothesize that hemostasis assessment can be un-blinded by Acoustic Radiation Force Impulse (ARFI) ultrasound. In this first of a two-part series, we present in vivo ARFI hemostasis imaging data obtained in relevant canine models of femoral artery puncture. Above arteriotomies, ARFI-induced displacements were large (3.5 to>5.0 μm) relative to surrounding soft tissue soon after needle removal, which was consistent with our expectation for pooled extravasated blood. ARFI-induced displacements above arteriotomies decreased in magnitude (to ∼ 2μm) some time after needle removal and suggested the onset of hemostasis. This preclinical investigation served as proof of concept and justification for a pilot human study, which is presented in part two of this series.

6G-5 ARFI Ultrasound for Characterizing Atherosclerosis

Cardiovascular disease (CVD) is the leading cause of death in the United States, with coronary artery disease and stroke alone accounting for 70% of CVD mortalities. Given this tremendous human impact, imaging technologies that enhance CVD outcomes by enabling earlier disease detection, monitoring the effects of therapeutic interventions, and delineating disease progression or regression are in critical need. We hypothesize that Acoustic Radiation Force Impulse (ARFI) ultrasound is efficacious for noninvasive characterization of atherosclerotic plaque and arterial walls in CVD assessment. To test this hypothesis, we performed ARFI imaging in three iliac arteries: 1) an excised familial hypercholesterolemic (FH) pig iliac with a raised focal atherosclerotic plaque, 2) an in vivo FH pig iliac with diffuse atherosclerosis, and 3) an in vivo control pig iliac with no known disease. In all three cases, our ARFI results were compared to matched immunohistochemistry, which showed a spatial correlation between collagen and elastin content and tissue mechanical property. This work supports the merit of additional investigations into ARFI imaging as a noninvasive, in vivo imaging technology for characterizing atherosclerotic plaque and arteries

5C-5 A Rigid Wall Approach to Physiologic Motion Rejection in Arterial Radiation Force Imaging

Physiologic motion corrupts measurements of induced tissue displacements and obscures tissue mechanical properties in radiation force ultrasound. Wall dilation and contraction with cardiac pulsation is especially disruptive to radiation force imaging the arterial system. We hypothesize that exploiting a rigid arterial wall model, which assumes long wavelength arterial pulse waves, will improve physiologic motion rejection in arterial radiation force imaging. Three rigid wall assuming filters (polynomial regression, principal component regression, and FIR high-pass filters) were compared to four filters that did not assume a rigid arterial wall (linear regression, quadratic regression, principal component regression, and FIR high-pass filters). The filters were tested using Field II generated data inclusive of simulated arterial wall motion combined with experimental acoustic radiation force impulse (ARFI) or shear wave elastography imaging (SWEI) displacement profiles. Performance metrics were sum of absolute differences (SAD) between original and filtered ARFI or SWEI displacement profiles in terms of total profile error, measured peak displacement error, measured recovery time error, and time-to-peak displacement error. Rigid wall assuming polynomial and principal component regression filters yielded the lowest SAD scores. The filters were also qualitatively compared on in vivo ARFI and SWEI data acquired in healthy pig iliac arteries.

Reverberation artifact rejection and masking in arterial ARFI imaging

In arterial ultrasound imaging, interpretation of plaque geometry may be distorted by reverberation artifacts in the lumen. Reverberation and arterial wall signals may be highly correlated, which precludes frequency domain or conventional regression filtering methods; however, decorrelation and rates vary. The variance of time derivatives in 1D axial cross-correlation (CC) and displacement (Disp) measures were exploited to reject the arterial lumen and reverberation artifact. Adaptively determined thresholds were applied to the variance of either individual or spatially clustered ARFI displacement profiles. The resulting binary masks were applied in vivo to six porcine arteries with varying degrees of reverberation artifact. Mask performance was measured as the percentage of the lumen rejected given at least 98% of each arterial wall remaining intact. The highest performing masks used the variance of the 2nd derivative of displacement or correlation with spatial clustering to preserve both arterial wall and soft tissue signals.

P2E-3 Blind Source Separation and K-Means Clustering for Vascular ARFI Image Segmentation, In Vivo and Ex Vivo

Blind source separation (BSS) is a time domain method for signal decomposition previously demonstrated in medical ultrasound for adaptive regression filtering. Just as BSS is relevant to clutter rejection by differentiating RF signals from moving blood versus arterial wall tissue, BSS is useful for distinguishing displacement profiles measured in tissue exhibiting different mechanical responses to radiation force. In concert with K-means clustering, an algorithm for partitioning N data points into K subsets, BSS can be employed for automated image segmentation via mechanical property in acoustic radiation force impulse (ARFI) ultrasound. We present BSS-based ARFI image segmentation in application to the peripheral vasculature. First, our segmentation method is validated using a synthetic data set with additive noise. Second, our method is demonstrated in an excised atherosclerotic familial hypercholesterolemic (FH) pig iliac artery with confirmation by matched immunohistochemistry. Finally, the method is applied to segmenting in vivo ARFI images in an atherosclerotic FH pig iliac artery as well as a human popliteal vein with no known disease. This work substantiates additional applications of BSS-based ARFI image segmentation

Reflected shear wave imaging of atherosclerosis

Atherosclerotic risk stratification may be improved by identifying soft lipid-rich or necrotic plaque regions, fibrous caps, calcium deposits, and other plaque components with disparate mechanical impedances. Mechanical impedance interfaces reflect acoustic radiation force (ARF)-induced shear waves. For the purpose of detecting these shear wave reflections, we developed a novel method as an adjunct to conventional ARFI called reflected shear wave imaging (RSWI). RSWI identifies shear wave reflections in tissue as inflections in 1D axial displacement profiles measured in the ARF region of excitation. This technique generates parametric images of shear wave reflections (SWRs) using only conventional 2D ARFI data sets. RSWI was performed on three familial hypercholesterolemic (FH) porcine iliac arteries, two ex vivo and one in vivo. Our results suggest that RSWI improves identification of soft, lipid-rich or necrotic plaque regions near fibrous cap, calcium, and collagen deposits. RSWI supports shear wave velocity (SWV) estimation, which may be useful for quantitative ARF-based imaging.

Comparison of multiple beam sequences in arterial ARFI imaging, ex vivo

Acoustic Radiation Force Impulse (ARFI) has been demonstrated for differentiating mechanical properties in a variety of tissues. To fully maximize the potential of ARFI imaging in the context of material characterization of atherosclerosis it is important to understand the benefits and drawbacks of various radiation force excitation and tracking methods. We investigated the impact of five excitation methods and two tracking methods of radiation force beam sequences in a pig model of hypercholesterolemic atherosclerosis. The pigs were either familial hypercholesterolemic (FH) or dietary hypercholesterolemic (DH). First, we compared two methods of A-line receiving: single receive (SRX) and parallel receive (ParRX) in a FH female pig. Second, ARFI excitations with varying F/#s of F/1, F/1.5, F/2, and F/3, were examined in another FH female. Lastly, to compare the utility of multiple ARFI excitations, both single excitation pulse ARFI (SP) and double excitation pulse ARFI (DP) were compared in a DH female. Comparing A-line receiving methods, SP-ParRX was observed to have lower spatial sensitivity to local variation of mechanical property than SP-SRX. Large excitation pulse F/#s were observed to yield more variability in measured ARFI parameters in the location of a large calcification and better differentiation of local variations in material content. DP ARFI provided useful insights that were supplemental to those provided by SP ARFI alone.