Joseph J. Fulton

Non-invasive in vivo characterization of human carotid plaques with acoustic radiation force impulse ultrasound: comparison with histology after endarterectomy.

Ischemic stroke from thromboembolic sources is linked to carotid artery atherosclerotic disease with a trend toward medical management in asymptomatic patients. Extent of disease is currently diagnosed by non-invasive imaging techniques that measure luminal stenosis, but it has been suggested that a better biomarker for determining risk of future thromboembolic events is plaque morphology and composition. Specifically, plaques that are composed of mechanically soft lipid/necrotic regions covered by thin fibrous caps are the most vulnerable to rupture. An ultrasound technique that non-invasively interrogates the mechanical properties of soft tissue, called acoustic radiation force impulse (ARFI) imaging, has been developed as a new modality for atherosclerotic plaque characterization using phantoms and atherosclerotic pigs, but the technique has yet to be validated in vivo in humans. In this preliminary study, in vivo ARFI imaging is presented in a case study format for four patients undergoing clinically indicated carotid endarterectomy and compared with histology. In two type Va plaques, characterized by lipid/necrotic cores covered by fibrous caps, mean ARFI displacements in focal regions were high relative to the surrounding plaque material, suggesting soft features were covered by stiffer layers within the plaques. In two type Vb plaques, characterized by heavy calcification, mean ARFI peak displacements were low relative to the surrounding plaque and arterial wall, suggesting stiff tissue. This pilot study illustrates the feasibility and challenges of transcutaneous ARFI for characterizing the material and structural composition of carotid atherosclerotic plaques via mechanical properties, in humans, in vivo.

Performance of acoustic radiation force impulse ultrasound imaging for carotid plaque characterization with histologic validation

Objective: Stroke is commonly caused by thromboembolic events originating from ruptured carotid plaque with vulnerable composition. This study assessed the performance of acoustic radiation force impulse (ARFI) imaging, a noninvasive ultrasound elasticity imaging method, for delineating the composition of human carotid plaque in vivo with histologic validation. Methods: Carotid ARFI images were captured before surgery in 25 patients undergoing clinically indicated carotid endarterectomy. The surgical specimens were histologically processed with sectioning matched to the ultrasound imaging plane. Three radiologists, blinded to histology, evaluated parametric images of ARFI‐induced peak displacement to identify plaque features such as necrotic core (NC), intraplaque hemorrhage (IPH), collagen (COL), calcium (CAL), and fibrous cap (FC) thickness. Reader performance was measured against the histologic standard using receiver operating characteristic curve analysis, linear regression, Spearman correlation (&rgr;), and Bland‐Altman analysis. Results: ARFI peak displacement was two‐to‐four‐times larger in regions of NC and IPH relative to regions of COL or CAL. Readers detected soft plaque features (NC/IPH) with a median area under the curve of 0.887 (range, 0.867–0.924) and stiff plaque features (COL/CAL) with median area under the curve of 0.859 (range, 0.771–0.929). FC thickness measurements of two of the three readers correlated with histology (reader 1: R2 = 0.64, &rgr; = 0.81; reader 2: R2 = 0.89, &rgr; = 0.75). Conclusions: This study suggests that ARFI is capable of distinguishing soft from stiff atherosclerotic plaque components and delineating FC thickness.

In vivo carotid plaque stiffness measurements with ARFI ultrasound in endarterectomy patients

Acoustic radiation force impulse (ARFI) ultrasound is an elasticity imaging technique that has the potential to identify vulnerable atherosclerotic plaque characteristics. Previous studies have shown that regions of high ARFI-induced displacement correspond to lipid/necrotic areas in plaques, whereas regions of low displacement correspond with fibrotic/calcified areas. In this work, we continue our analysis of ARFI images captured from patients undergoing carotid endarterectomy. ARFI imaging of carotid plaque was performed prior to surgery, and extracted specimens were histologically processed and matched to the ultrasound imaging plane. ARFI images and histological slides were annotated independently for various features including necrotic core, calcification, fibrosis and fibrous cap, and wide hemorrhage. Results are presented for a number of advanced plaque types (Va, Vb, and VI), and ARFI-derived fibrous cap thickness measurements are compared quantitatively to histology. Results suggest ARFI is capable of measuring fibrous cap thickness with a mean positive bias of 0.09 ± 0.12 mm, and may be capable of identifying ruptured plaque.

In vivo characterization of atherosclerotic plaque of human carotid arteries with histopathological correlation using ARFI ultrasound

Atherosclerotic plaque characterization with acoustic radiation force impulse (ARFI) imaging has recently been developed using phantoms and atherosclerotic pigs, but has yet to be validated in vivo in humans. We present initial results from an ongoing clinical trial investigating in vivo ARFI imaging of human carotid plaque with spatially-matched histopathology. Patients undergoing clinically-indicated carotid endarterectomy (CEA) were recruited from UNC Hospitals and imaged with ARFI prior to surgery. After surgery, the extracted specimen was sectioned according to noted arterial geometry for spatial registration to the ultrasound imaging plane and processed histologically. In two symptomatic patients, plaques were composed of a mixture of small and large necrotic cores, mild intra-plaque hemorrhage, and fibrosis. Mean ARFI peak displacements were observed to be two to three times higher in regions corresponding to either necrotic core or intra-plaque hemorrhage compared to regions of dense fibrosis or calcification. In an asymptomatic patient with predominantly calcified plaque, mean ARFI peak displacements were small (~1-2 μm) suggesting stiff tissue. The results of this study indicate that areas of relatively large displacement by ARFI imaging correlate with lipid/necrotic cores and/or inflammation, which may confer an increased chance of plaque rupture and future ischemic event. This work demonstrates the feasibility of transcutaneous ARFI for characterizing the material and structural composition of carotid atherosclerotic plaques via mechanical properties, in humans, in vivo.

Carotid plaque characterization with ARFI imaging: Blinded reader study

Stroke is commonly caused by thromboembolic events originating from vulnerable atherosclerotic plaque in the carotid vasculature. The purpose of this study was to evaluate the ability of acoustic radiation force impulse (ARFI) imaging, a noninvasive elastography imaging technique, to assess the composition of carotid artery plaques using histologic examination as the gold standard. Twenty-five patients undergoing carotid endarterectomy (CEA) were enrolled and imaged with ARFI. After surgery, extracted specimens were histologically processed and matched to the ultrasound imaging plane. Parametric 2D ARFI images of peak displacement (PD) were evaluated by three radiologists blinded to the histology result. Receiver operating characteristic (ROC) curve analysis was performed, and area under the ROC curve (AUC) was taken as a metric of performance for detecting plaque features such as necrotic core (NC), intraplaque hemorrhage (IPH), collagen (COL), and calcium (CAL). Additionally, linear regression was performed on fibrous cap (FC) thickness measurements. Areas of plaque with NC and IPH were observed to have substantially increased ARFI PD (2× to 4×) compared to areas of plaque with COL or CAL. Median AUC for detecting soft plaque features (NC/IPH) was 0.887 (range: 0.867 - 0.924) and stiff plaque features (COL/CAL) was 0.859 (range: 0.771 - 0.929). FC thickness measured by two of the three radiologists matched closely with histology (reader 1: R2 = 0.64; reader 2: R2 = 0.89). This study suggests that ARFI is capable of distinguishing soft from stiff compositional elements of atherosclerotic plaques and may be relevant to improving plaque risk assessment.