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.

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 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.

In-hospital statin underutilization among high-risk patients: delayed uptake of the 2013 cholesterol guidelines in a U.S. cohort.

OBJECTIVES: Clinician utilization of the 2013 cholesterol lowering guidelines remains variable and unknown. We sought to examine statin prescribing patterns and compare rates among specialists who treat high-risk cardiovascular patients admitted to the hospital. METHODS: We retrospectively (via chart review) examined four specialty groups: (i) Cardiology, (ii) Cardiovascular or Vascular (CV) Surgery, (iii) Neurology, and (iv) Internal Medicine. Adult patients were included based on a discharge diagnosis of acute coronary syndrome, coronary artery bypass graft surgery, carotid endarterectomy, acute ischemic stroke, transient ischemic attack, or high-risk chest pain. Prescribing patterns were evaluated 6 months and 18 months after the release of the 2013 guidelines. High-intensity statin was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg per day. RESULTS: 632 patients were included in our study. The following percentages of patients were discharged on high-intensity statin (6 months; 18 months): (i) Cardiology (80%; 85%), (ii) CV Surgery (52%, 65%), (iii) Neurology (59%; 66%), and (iv) Internal Medicine (45%; 48%). Among the four groups, Cardiology was the most likely to discharge patients on high-intensity statin (p < 0.001) in 2014 and in 2015. Cardiology, CV Surgery, and Neurology significantly increased the percentage of patients on high-intensity statin from pre-admission to time of discharge in both years. CONCLUSION: High-intensity statin therapy is underutilized among high-risk cardiovascular patients admitted to the hospital. Variations exist in prescribing patterns of different specialties who manage high-risk populations. This data can be used to test quality improvement interventions to improve rates of high-intensity statin utilization among high-risk patients prior to hospital discharge.

Safety of ultrasound contrast agents in patients with known or suspected cardiac shunts.

Contrast-enhanced ultrasound imaging is a radiation-free diagnostic tool that uses biocompatible ultrasound contrast agents (UCAs) to improve image clarity. UCAs, which do not contain dye, often salvage "technically difficult" ultrasound scans, increasing the accuracy and reliability of a front-line ultrasound diagnosis, reducing unnecessary downstream testing, lowering overall health care costs, changing therapy, and improving patient care. Two UCAs currently are approved and regulated by the US Food and Drug Administration. They have favorable safety profiles and risk/benefit ratios in adult and pediatric populations, including compromised patients with severe cardiovascular diseases. Nevertheless, these UCAs are contraindicated in patients with known or suspected right-to-left, bidirectional, or transient right-to-left cardiac shunts. These patients, who constitute 10% to 35% of the general population, typically receive no UCAs when they undergo echocardiography. If their echocardiographic images are suboptimal, they may receive inappropriate diagnosis and treatment, or they may be referred for additional diagnostic testing, including radiation-based procedures that increase their lifetime risk for cancer or procedures that use contrast agents containing dye, which may increase the risk for kidney damage. An exhaustive review of current peer-reviewed research demonstrated no scientific basis for the UCA contraindication in patients with known or suspected cardiac shunts. Initial safety concerns were based on limited rodent data and speculation related to macroaggregated albumin microspheres, a radioactive nuclear imaging agent with different physical and chemical properties and no relation to UCAs. Radioactive macroaggregated albumin is not contraindicated in adult or pediatric patients with cardiac shunts and is routinely used in these populations. In conclusion, the International Contrast Ultrasound Society Board recommends removal of the contraindication to further the public interest in safe, reliable, radiation-free diagnostic imaging options for patients with known or suspected cardiac shunts and to reduce their need for unnecessary downstream testing.

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.

Detection of adventitial vasa vasorum and intraplaque neovascularization in carotid atherosclerotic lesions with contrast-enhanced ultrasound and their role in atherosclerosis.

INTRODUCTION: The development of new surrogate markers of atherosclerosis is a crucial goal in the clinical setting, as they may allow physicians to recognize unstable lesions early and identify individuals with vulnerable or unstable lesions who bear an increased risk of future cardio--and cerebrovascular complications. These surrogate markers should be capable of being measured noninvasively using safe and reliable methods. Recently, Nambi et al. demonstrated how the combined measurement of carotid intima media thickness (CIMT) and occurrence of carotid plaques improves the risk prediction of cardiovascular outcomes. These results confirm the value of carotid ultrasound (US) when combined with traditional Framingham risk factors in assessing a patient's risk for atherosclerotic disease. Contrast-enhanced ultrasound (CEUS) is a new imaging approach that is evolving and may become a standard clinical tool for further atherosclerotic risk stratification in the future. The contrast agents used in US imaging are safe, commercially available, and approved for use in echocardiography by the FDA. Thus, CEUS is technically feasible with existing approved commercial equipment and can be performed at the bedside or in an outpatient setting. However, US contrast agents are not yet approved by the FDA for visualization and assessment of the carotid artery and its associated pathologies. The cost effectiveness of CEUS has been shown in the context of gastrointestinal imaging, and CEUS of carotid atherosclerotic lesions is emerging as an approach to complement unenhanced US imaging. By providing the direct visualization of adventitial vasa vasorum (VV) and intraplaque neovascularization, CEUS is capable of depicting two new surrogate markers of atherosclerosis - namely, adventitial VV and intraplaque neovascularization.

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.

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.

Effects of consumption of pomegranate juice on carotid intima-media thickness in men and women at moderate risk for coronary heart disease.

This randomized, double-blind, parallel trial assessed the influence of pomegranate juice consumption on anterior and posterior carotid intima-media thickness (CIMT) progression rates in subjects at moderate risk for coronary heart disease. Subjects were men (45 to 74 years old) and women (55 to 74 years old) with > or =1 major coronary heart disease risk factor and baseline posterior wall CIMT 0.7 to 2.0 mm, without significant stenosis. Participants consumed 240 ml/day of pomegranate juice (n = 146) or a control beverage (n = 143) for up to 18 months. No significant difference in overall CIMT progression rate was observed between pomegranate juice and control treatments. In exploratory analyses, in subjects in the most adverse tertiles for baseline serum lipid peroxides, triglycerides (TGs), high-density lipoprotein (HDL) cholesterol, TGs/HDL cholesterol, total cholesterol/HDL cholesterol, and apolipoprotein-B100, those in the pomegranate juice group had significantly less anterior wall and/or composite CIMT progression versus control subjects. In conclusion, these results suggest that in subjects at moderate coronary heart disease risk, pomegranate juice consumption had no significant effect on overall CIMT progression rate but may have slowed CIMT progression in subjects with increased oxidative stress and disturbances in the TG-rich lipoprotein/HDL axis.

Contrast-enhanced ultrasound imaging of atherosclerotic carotid plaque neovascularization: a new surrogate marker of atherosclerosis?

An atherosclerotic plaque requires a nutrient blood supply, which is predominantly derived from arterial vasa vasorum. A variety of factors (environmental and genetic) contribute to the initiation and growth of atherosclerosis within vessel walls. Chemotactic factors, such as tissue ischemic and hypoxic factors, stimulate the release of vascular endothelial growth factor (VEGF) proteins, resulting in vessel wall angiogenesis. These developments often precede the formation of the luminal plaque. In this report, we describe the use of contrast-enhanced carotid ultrasound (CECU) imaging for the detection and quantification of intra-plaque neovascularization. The efficacy of CECU was measured against the neovascular density observed within the tissue specimens obtained at the time of carotid endarterectomy surgery. The objective of this study was to provide a histologic correlation between CECU and carotid artery atherosclerotic plaque neovascularization. Fifteen patients with significant atherosclerotic carotid artery disease received a CECU examination prior to undergoing a carotid endarterectomy (CEA). Two patients received bilateral endarterectomies, resulting in a total of 17 cases. At the time of surgery, carotid plaque samples were surgically removed and stained with specific vascular markers (CD31, CD34, von Willebrand factor, and hemosiderin) designed to identify the presence and degree of neovascularization. The intra-plaque neovascularization recorded on preoperative CECU was correlated with the degree of neovascularization noted in the tissue specimens. The CECU neovascularization was correlated to CD31-stained tissue specimens. This correlation value was 0.68 using Spearman's rank method. When CECU results were correlated with the other histologic markers (CD34, von Willebrand factor, and hemosiderin), a correlation of 0.50 was obtained. In conclusion, contrast-enhanced carotid ultrasound correlated to the presence and degree of intra-plaque neovascularization as determined from histology specimens.

Role of surrogate markers in assessing patients with diabetes mellitus and the metabolic syndrome and in evaluating lipid-lowering therapy.

Diabetes mellitus and the metabolic syndrome (MS) are reaching epidemic proportions in the United States, and cardiovascular disease continues to be the leading cause of death among patients with diabetes. A range of noninvasive screening tools may help reduce the morbidity and mortality of patients with diabetes because of early detection of subclinical cardiovascular disease and active monitoring of the effectiveness of therapy. Surrogate markers of subclinical disease include conventional and contrast-enhanced ultrasound imaging of carotid artery intima-media thickness (c-IMT), 2-dimensional echocardiography, coronary artery calcium imaging, cardiac magnetic resonance imaging, ankle-brachial indices, and brachial artery reactivity testing. Because these noninvasive imaging tools are relatively comfortable and entail relatively low risk to the patient, they are ideal for initial screening and for the repeated imaging that is required for monitoring the effectiveness of therapy. Moreover, when used in large numbers of patients with diabetes, prediabetes, and the MS, these imaging tools may be useful in developing and validating thresholds for the use of lipid-lowering therapy as well as clear therapeutic goals for this population. In addition, contrast-enhanced c-IMT scans now produce real-time images of the vasa vasorum and neovascularization of atherosclerotic plaque, potentially causing a paradigm shift in our view of the genesis of atherosclerosis and affecting treatment options for all populations. Thus, surrogate markers may not only help improve individual patient outcomes, they also may help direct scarce medical resources to maximize medical benefits, improve overall medical care, and minimize costs and untoward side effects.

Noninvasive surrogate markers of atherosclerosis.

Noninvasive imaging techniques offer a unique opportunity to study the relation of surrogate markers to the development of atherosclerosis. These noninvasive imaging modalities include: (1) carotid artery, coronary, and aorta imaging; (2) left ventricular echocardiography imaging; (3) electron-beam computed tomography; (4) magnetic resonance imaging; and (5) ankle-brachial index. Because the incidence of coronary artery disease is a function of the development and progression of atherosclerosis, the use of noninvasive surrogate markers of atherosclerosis can aid in the diagnosis of cardiovascular disease through the identification of subclinical disease. Noninvasive imaging techniques provide an approach for identifying high-risk individuals who may benefit from active intervention to prevent clinical disease.