3D-Arterial analysis software and CEUS in the assessment of severity and vulnerability of carotid atherosclerotic plaque: a comparison with CTA and histopathology.

PURPOSE: Our purpose is to assess Multiparametric Ultrasound (MPUS) efficacy for evaluation of carotid plaque vulnerability and carotid stenosis degree in comparison with Computed Tomography angiography (CTA) and histology. MATERIAL AND METHODS: 3D-Arterial Analysis is a 3D ultrasound software that automatically provides the degree of carotid stenosis and a colorimetric map of carotid plaque vulnerability. We enrolled 106 patients who were candidates for carotid endarterectomy. Prior to undergoing surgery, all carotid artery plaques were evaluated with Color-Doppler-US (CDUS), Contrast-Enhanced Ultrasound (CEUS), and 3D Arterial analysis (3DAA) US along with Computerized Tomographic Angiography (CTA) to assess the carotid artery stenosis degree. Post-surgery, the carotid specimens were fixed with 10% neutral buffered formalin solution, embedded in paraffin and used for light microscopic examination to assess plaque vulnerability morphological features. RESULTS: The results of the CTA examinations revealed 91 patients with severe carotid stenoses with a resultant diagnostic accuracy of 82.3% for CDUS, 94.5% for CEUS, 98.4% for 3DAA, respectively. The histopathological examination showed 71 vulnerable plaques with diagnostic accuracy values of 85.8% for CDUS, 93.4% for CEUS, 90.3% for 3DAA, 92% for CTA, respectively. CONCLUSIONS: The combination of CEUS and 3D Arterial Analysis may provide a powerful new clinical tool to identify and stratify "at-risk" patients with atherosclerotic carotid artery disease, identifying vulnerable plaques. These applications may also help in the postoperative assessment of treatment options to manage cardiovascular risks.

Contrast-enhanced ultrasound in pediatric echocardiography.

The safety and benefits of cardiac contrast-enhanced ultrasound (CEUS) have been demonstrated in children and adolescents for a variety of clinical indications, including congenital heart disease. Cardiac CEUS is performed with US and the intravenous administration of ultrasound contrast agents (UCAs). It improves transthoracic echocardiography, which can be challenging in children and adults with acoustic window limitations (e.g., from obesity) and alterations in chest wall and cardiac geometry (e.g., from prior surgical procedures). Cardiac CEUS is also used to evaluate ischemia in the follow-up of congenital and acquired heart disease. In 2019, the United States Food and Drug Administration (FDA) approved a UCA for pediatric echocardiography. This article focuses on the clinical applications of UCAs in pediatric and adult echocardiography, outlining its diagnostic value, safety and potential for future applications.

Pediatric contrast-enhanced ultrasound: shedding light on the pursuit of approval in the United States.

For two decades, pediatric contrast US has been well accepted throughout Europe and other parts of the world outside the United States because of its high diagnostic efficacy and extremely favorable safety profile. This includes intravenous (IV) administration, contrast-enhanced US (CEUS) and the intravesical application, contrast-enhanced voiding urosonography (ceVUS). However, the breakthrough for pediatric contrast US in the United States did not come until 2016, when the U.S. Food and Drug Administration (FDA) approved the first pediatric indication for a US contrast agent. This initial approval covered the use of Lumason (Bracco Diagnostics, Monroe Township, NJ) for the evaluation of focal liver lesions via IV administration in children. A second pediatric indication followed shortly thereafter, when the FDA extended the use of Lumason for assessing known or suspected vesicoureteral reflux via intravesical application in children. Both initial pediatric approvals were granted without prospective pediatric clinical trials, based instead on published literature describing favorable safety and efficacy in children. Three years later, in 2019, the FDA approved Lumason for pediatric echocardiography following a clinical trial involving a total of 12 subjects at 2 sites. The story of how we achieved these FDA approvals spans more than a decade and involves the extraordinary dedication of two professional societies, namely the International Contrast Ultrasound Society (ICUS) and the Society for Pediatric Radiology (SPR). Credit also must be given to the FDA staff for their commitment to the welfare of children and their openness to compelling evidence that contrast US is a safe, reliable, radiation-free imaging option for our pediatric patients. Understanding the history of this approval process will impact the practical application of US contrast agents, particularly when expanding off-label indications in the pediatric population. This article describes the background of the FDA's approval of pediatric contrast US applications to better illuminate the potential pathways to approvals of future indications.

Use of ultrasound enhancing agents in transesophageal echocardiography to improve interpretive confidence of left atrial appendage thrombus.

BACKGROUND: The value of ultrasound enhancing agents (UEA) in patients undergoing transesophageal echocardiography (TEE) for the exclusion of left atrial appendage (LAA) thrombi prior to direct current cardioversion (DCCV) is evolving. METHODS: We retrospectively identified 88 consecutive TEEs, where a commercial UEA was used during LAA interrogation. De-identified non-enhanced (pre-UEA) and enhanced cine loop images (post-UEA) from the same subjects were randomly reviewed by four expert readers in a blinded fashion. RESULTS: In 33% of the cases, UEA use was associated with a statistically insignificant improvement in physician confidence (scale, 0-3) in determining the presence or absence of a LAA thrombus (P = 0.071). In instances where non-enhanced images yielded an uncertain interpretation or when the left atrium contained spontaneous echo contrast (SEC), UEA use was associated with an improvement in interpretive confidence in 49% (P < 0.001) and 41% of the cases (P = 0.001), respectively. Overall, the absolute rate of hypothetical decision to proceed with DCCV rose by 9% with the application of UEA (P = 0.004). In instances where non-enhanced images were interpreted with limited confidence or when SEC was present, there were absolute increases of 16% (P < 0.001) and 21% (P < 0.001) in hypothetical procession to DCCV, respectively. In cases of a combination of limited interpretive confidence and SEC, UEA use was associated with a 29% absolute increase in the rate of procession to DCCV (P < 0.001). CONCLUSIONS: In patients undergoing TEE interrogation of the LAA, the use of UEA is associated with an increase in the level of interpretive confidence and higher rates of theoretical procession to DCCV.

Drug and Gene Delivery using Sonoporation for Cardiovascular Disease.

Using the improvements made in diagnostic contrast enhanced ultrasound, researchers have made significant progress in the field of ultrasound-mediated sonoporation for drug delivery. Many programs take advantage of commercial products; both ultrasound imaging systems and contrast agents to better enable translation from preclinical to first-in-man studies (Kotopoulis et al., Med Phys 40:072902, 2013). Particularly well-suited targets for this novel therapy are diseases of the cardiovascular system. This chapter will highlight several recent studies addressing treatment of both acute and chronic conditions.

Soluble urokinase plasminogen activator receptor and cardiotoxicity in doxorubicin-treated breast cancer patients: a prospective exploratory study.

BACKGROUND: Soluble urokinase plasminogen activator receptor is an inflammatory biomarker that may prognosticate cardiovascular outcomes. We sought to determine the associations between soluble urokinase plasminogen activator receptor and established markers of cardiotoxicity in breast cancer patients receiving doxorubicin. METHODS: We conducted a prospective cohort study of women with newly diagnosed breast cancer receiving standard-dose doxorubicin (240 mg/m2) at Rush University Medical Center and Rush Oak Park Hospital (Chicago, IL) between January 2017 and May 2019. Left ventricular ejection fraction, global longitudinal strain, and cardiac biomarkers (N-terminal prohormone B-type natriuretic peptide, troponin-I, and high-sensitivity C-reactive protein) were measured at baseline and at intervals up to 12-month follow-up after end of treatment. The associations between soluble urokinase plasminogen activator receptor and these endpoints were evaluated using multivariable mixed effects linear regression. RESULTS: Our study included 37 women (mean age 47.0 ± 9.3 years, 60% white) with a median baseline soluble urokinase plasminogen activator receptor level of 2.83 ng/dL. No participant developed cardiomyopathy based on serial echocardiography by one-year follow-up. The median percent change in left ventricular strain was -4.3% at 6-month follow-up and absolute changes in cardiac biomarkers were clinically insignificant. There were no significant associations between soluble urokinase plasminogen activator receptor and these markers of cardiotoxicity (all p > 0.05). CONCLUSIONS: In this breast cancer cohort, doxorubicin treatment was associated with a very low risk for cardiotoxicity. Across this narrow range of clinical endpoints, soluble urokinase plasminogen activator receptor was not associated with markers of subclinical cardiotoxicity. Further studies are needed to clarify the prognostic utility of soluble urokinase plasminogen activator receptor in doxorubicin-associated cardiomyopathy and should include a larger cohort of leukemia and lymphoma patients who receive higher doses of doxorubicin.

Ultrasound-mediated targeted drug delivery: recent success and remaining challenges.

The potential clinical value of developing a novel, nonviral, ultrasound-directed gene and drug delivery system is immense. Investigators soon will initiate clinical trials with the goal of treating a wide variety of maladies using noninvasive, ultrasound-based technology. The ongoing, scientific validation associated with promising preclinical success portents a novel range of therapeutics. The clinical utility and eventual clinical successes await vigorous testing. This review highlights the recent successes and challenges within the field of ultrasound-mediated drug delivery.

Safety of contrast-enhanced ultrasound in children for non-cardiac applications: a review by the Society for Pediatric Radiology (SPR) and the International Contrast Ultrasound Society (ICUS).

The practice of contrast-enhanced ultrasound in children is in the setting of off-label use or research. The widespread practice of pediatric contrast-enhanced US is primarily in Europe. There is ongoing effort by the Society for Pediatric Radiology (SPR) and International Contrast Ultrasound Society (ICUS) to push for pediatric contrast-enhanced US in the United States. With this in mind, the main objective of this review is to describe the status of US contrast agent safety in non-cardiac applications in children. The five published studies using pediatric intravenous contrast-enhanced US comprise 110 children. There is no mention of adverse events in these studies. From a European survey 948 children can be added. In that survey six minor adverse events were reported in five children. The intravesical administration of US contrast agents for diagnosis of vesicoureteric reflux entails the use of a bladder catheter. Fifteen studies encompassing 2,951 children have evaluated the safety of intravesical US contrast agents in children. A European survey adds 4,131 children to this group. No adverse events could be attributed to the contrast agent. They were most likely related to the bladder catheterization. The existing data on US contrast agent safety in children are encouraging in promoting the widespread use of contrast-enhanced US.

Contrast-enhanced ultrasound for assessing carotid atherosclerotic plaque lesions.

OBJECTIVE: Contrast-enhanced ultrasound that is used to assess atherosclerotic carotid plaques improves visualization of vessel wall irregularities and provides direct visualization of intraplaque neovascularization. This article illustrates the use of contrast-enhanced ultrasound in the assessment of carotid atherosclerotic lesions. CONCLUSION: Contrast-enhanced ultrasound is a new, noninvasive, and safe procedure for imaging carotid atherosclerotic lesions. It is a valuable tool for evaluating the vulnerable plaque at risk for rupture and for evaluating both the development and severity of systemic atherosclerotic disease.

CEUS cardiac exam protocols International Contrast Ultrasound Society (ICUS) recommendations.

The present CEUS Cardiac Exam Protocols represent the first effort to promulgate a standard set of protocols for optimal administration of ultrasound enhancing agents (UEAs) in echocardiography, based on more than two decades of experience in the use of UEAs for cardiac imaging. The protocols reflect current clinical CEUS practice in many modern echocardiography laboratories throughout the world. Specific attention is given to preparation and dosing of three UEAs that have been approved by the United States Food and Drug Administration (FDA) and additional regulatory bodies in Europe, the Americas and Asia-Pacific. Consistent with professional society guidelines (J Am Soc Echocardiogr 31:241-274, 2018; J Am Soc Echocardiogr 27:797-810, 2014; Eur Heart J Cardiovasc Imaging 18:1205, 2017), these protocols cover unapproved "off-label" uses of UEAs-including stress echocardiography and myocardial perfusion imaging-in addition to approved uses. Accordingly, these protocols may differ from information provided in product labels, which are generally based on studies performed prior to product approval and may not always reflect state of the art clinical practice or guidelines.

Correlation of carotid artery atherosclerotic lesion echogenicity and severity at standard US with intraplaque neovascularization detected at contrast-enhanced US.

PURPOSE: To correlate echogenicity and severity of atherosclerotic carotid artery lesions at standard ultrasonography (US) with the degree of intraplaque neovascularization at contrast material-enhanced (CE) US. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the local ethics committee, and all patients provided informed consent. A total of 175 patients (113 [65%] men, 62 [35%] women; mean age, 67 years ± 10 [standard deviation]) underwent standard and CE US of the carotid artery. Lesion echogenicity (class I to IV), degree of stenosis, and maximal lesion thickness were evaluated for each documented atherosclerotic lesion. The degree of intraplaque neovascularization at CE US was categorized as absent (grade 1), moderate (grade 2), or extensive (grade 3). Correlation of neovascularization with echogenicity, degree of stenosis, and maximal lesion thickness was made by using Spearman ρ and χ(2) test for trend. RESULTS: In a total of 293 atherosclerotic lesions, echogenicity was inversely correlated with grade of intraplaque neovascularization (ρ = -0.199, P < .001). More echolucent lesions had a higher degree of neovascularization compared with more echogenic ones (P < .001). The degree of stenosis was significantly correlated with grade of intraplaque neovascularization (ρ = 0.157, P = .003). Lesions with higher degree of stenosis had higher grade of neovascularization (P = .008), and maximal lesion thickness increased with the grade of neovascularization (P < .001) and was significantly correlated with grade of neovascularization (ρ = 0.233, P < .001). CONCLUSION: Neovascularization visualized with CE US correlates with lesion severity and with morphologic features of plaque instability, contributing to the concept that more vulnerable plaques are more likely to have a greater degree of neovascularization. Therefore, CE US may be a valuable tool for further risk stratification of echolucent atherosclerotic lesions and carotid artery stenosis of different degrees. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10101008/-/DC1.

Vasa vasorum and plaque neovascularization on contrast-enhanced carotid ultrasound imaging correlates with cardiovascular disease and past cardiovascular events.

BACKGROUND AND PURPOSE: Histological data associate proliferation of adventitial vasa vasorum and intraplaque neovascularization with vulnerable plaques represented by symptomatic vascular disease. In this observational study, the presence of carotid intraplaque neovascularization and adventitial vasa vasorum were correlated with the presence and occurrence of cardiovascular disease (CVD) and events (CVE). METHODS: The contrast-enhanced carotid ultrasound examinations of 147 subjects (mean age 64+/-11 years, 61% male) were analyzed for the presence of intraluminal plaque, plaque neovascularization (Grade 1=absent; Grade 2=present), and degree of adventitial vasa vasorum (Grade 1=absent, Grade 2=present). These observations were correlated with preexisting cardiovascular risk factors, presence of CVD, and history of CVE (myocardial infarction and transient ischemic attack/stroke). RESULTS: The presence of intraluminal carotid plaque was directly correlated to cardiovascular risk factors, CVD, and CVE (P<0.05). Adventitial vasa vasorum Grade 2 was associated with significant more subjects with CVD than vasa vasorum Grade 1 (73 versus 54%, P=0.029). Subjects with intraplaque neovascularization Grade 2 had significantly more often a history of CVE than subjects with intraplaque neovascularization Grade 1 (38 versus 20%, P=0.031). Multivariate logistic regression analysis revealed that presence of plaque was significantly associated with CVD (odds ratio 4.7, 95% CI 1.6 to 13.8) and intraplaque neovascularization grade 2 with CVE (odds ratio 4.0, 95% CI 1.3 to 12.6). CONCLUSIONS: The presence and degree of adventitial vasa vasorum and plaque neovascularization were directly associated with CVD and CVE in a retrospective study of 147 patients undergoing contrast-enhanced carotid ultrasound.

Molecular imaging of inflammation and intraplaque vasa vasorum: a step forward to identification of vulnerable plaques?

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed.

Contrast-enhanced ultrasound for imaging vasa vasorum: comparison with histopathology in a swine model of atherosclerosis.

AIM: To evaluate the agreement between contrast-enhanced ultrasound imaging and histopathology in an animal model of atherosclerosis. METHODS AND RESULTS: Atherosclerosis was studied in both femoral arteries of four Rapacz familial hypercholesterolaemia (RFH) swine. Contrast-enhanced ultrasound imaging of the eight femoral arteries was performed at baseline and at 5, 12, 26, and 43 weeks follow-up after percutaneous transluminal stimulation of atherosclerosis to assess the progression of intima-media thickness (IMT) and the density and extent of the vasa vasorum network. Contrast-enhanced ultrasound imaging allowed an early detection of atherosclerosis and showed a significant gradual progression of atherosclerosis over time. IMT increased from 0.22 +/- 0.05 mm at baseline to 0.45 +/- 0.06 mm (P < 0.001) at follow-up. The density of the vasa vasorum network increased during follow-up and was significantly higher in advanced than in early atherosclerosis. The findings with contrast-enhanced ultrasound were confirmed by histopathological specimens of the arterial wall. CONCLUSION: Contrast-enhanced ultrasound is effective for in vivo detection of vasa vasorum in atherosclerotic plaques in the RFH swine model. After stimulation of atherosclerosis, contrast-enhanced ultrasound demonstrated a significantly increased IMT and significantly increased density of the vasa vasorum network in the developing atherosclerotic plaque, which was validated by histology.

New advances in noninvasive imaging of the carotid artery: CIMT, contrast-enhanced ultrasound, and vasa vasorum.

Carotid ultrasound measurement of carotid intima-media thickness (CIMT) and detection of plaques is a useful method to better assess cardiovascular disease risk status, especially in those at intermediate risk. We discuss the use CIMT and other emerging techniques such as contrast-enhanced carotid ultrasound imaging in the evaluation of the carotid artery and its value in cardiovascular disease.

Contrast-Enhanced Ultrasound to Assess Carotid Intraplaque Neovascularization.

Contrast-enhanced ultrasound (CEUS) is increasingly being used to identify patients with carotid plaques that are vulnerable to rupture, so-called vulnerable atherosclerotic plaques, by assessment of intraplaque neovascularization. A complete overview of the strengths and limitations of carotid CEUS is currently not available. The aim of this systematic review was to provide a complete overview of existing publications on the role of CEUS in assessment of carotid intraplaque neovascularization. The systematic review of the literature yielded 52 studies including a total of 4660 patients (mean age: 66 y, 71% male) who underwent CEUS for the assessment of intraplaque neovascularization. The majority of the patients (76%) were asymptomatic and had no history of transient ischemic attack (TIA) or stroke. The assessment of intraplaque neovascularization was mostly performed using a visual scoring system; several studies used time-intensity curves or dedicated quantification software to optimize analysis. In 17 studies CEUS was performed in patients before carotid surgery (endarterectomy), allowing a comparison of pre-operative CEUS findings with histologic analysis of the tissue sample that is removed from the carotid artery. In a total of 576 patients, the CEUS findings were compared with histopathological analysis of the plaque after surgery. In 16 of the 17 studies, contrast enhancement was found to correlate with the presence and degree of intraplaque neovascularization on histology. Plaques with a larger amount of contrast enhancement had significantly increased density of microvessels in the corresponding region on histology. In conclusion, CEUS is a readily available imaging modality for the assessment of patients with carotid atherosclerosis, providing information on atherosclerotic plaques, such as ulceration and intraplaque neovascularization, which may be clinically relevant. The ultimate clinical goal is the early identification of carotid atherosclerosis to start early preventive therapy and prevent clinical complications such as TIA and stroke.

Recommendations for the Assessment of Carotid Arterial Plaque by Ultrasound for the Characterization of Atherosclerosis and Evaluation of Cardiovascular Risk: From the American Society of Echocardiography.

Atherosclerotic plaque detection by carotid ultrasound provides cardiovascular disease risk stratification. The advantages and disadvantages of two-dimensional (2D) and three-dimensional (3D) ultrasound methods for carotid arterial plaque quantification are reviewed. Advanced and emerging methods of carotid arterial plaque activity and composition analysis by ultrasound are considered. Recommendations for the standardization of focused 2D and 3D carotid arterial plaque ultrasound image acquisition and measurement for the purpose of cardiovascular disease stratification are formulated. Potential clinical application towards cardiovascular risk stratification of recommended focused carotid arterial plaque quantification approaches are summarized.

Carotid intraplaque neovascularization predicts coronary artery disease and cardiovascular events.

AIMS: It is thought that the majority of cardiovascular (CV) events are caused by vulnerable plaque. Such lesions are rupture prone, in part due to neovascularization. It is postulated that plaque vulnerability may be a systemic process and that vulnerable lesions may co-exist at multiple sites in the vascular bed. This study sought to examine whether carotid plaque vulnerability, characterized by contrast-enhanced ultrasound (CEUS)-assessed intraplaque neovascularization (IPN), was associated with significant coronary artery disease (CAD) and future CV events. METHODS AND RESULTS: We investigated carotid IPN using carotid CEUS in 459 consecutive stable patients referred for coronary angiography. IPN was graded based on the presence and location of microbubbles within each plaque (0, not visible; 1, peri-adventitial; and 2, plaque core). The grades of each plaque were averaged to obtain an overall score per patient. Coronary plaque severity and complexity was also determined angiographically. Patients were followed for 30 days following their angiogram. This study found that a higher CEUS-assessed carotid IPN score was associated with significant CAD (≥50% stenosis) (1.8 ± 0.4 vs. 0.5 ± 0.6, P < 0.0001) and greater complexity of coronary lesions (1.7 ± 0.5 vs. 1.3 ± 0.8, P < 0.0001). Furthermore, an IPN score ≥1.25 could predict significant CAD with a high sensitivity (92%) and specificity (89%). The Kaplan-Meier analysis demonstrated a significantly higher proportion of participants having CV events with an IPN score ≥1.25 (P = 0.004). CONCLUSION: Carotid plaque neovascularization was found to be predictive of significant and complex CAD and future CV events. CEUS-assessed carotid IPN is a clinically useful tool for CV risk stratification in high-risk cardiac patients.