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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.

ABSTRACTObjectives: 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.

Contrast-enhanced ultrasonography (CEUS) is a rapidly evolving modality for imaging carotid artery disease and systemic atherosclerosis. CEUS coupled with diagnostic ultrasonography predicts the degree of carotid artery stenosis and is comparable with computed tomography and magnetic resonance angiography. This article reviews the literature on the evolving role of CEUS for the identification and characterization of carotid plaques with an emphasis on detection of intra-plaque neovascularization and related high-risk morphologic features notably present in symptomatic patients. CEUS carotid imaging may play a prominent additive role in risk stratifying patients and serve as a powerful tool for monitoring therapeutic interventions.

Ultrasound contrast agents (UCAs) are currently used throughout the world in both clinical and research settings. The concept of contrast-enhanced ultrasound imaging originated in the late 1960s, and the first commercially available agents were initially developed in the 1980s. Today's microbubbles are designed for greater utility and are used for both approved and off-label indications. In October 2007, the US Food and Drug Administration (FDA) imposed additional product label warnings that included serious cardiopulmonary reactions, several new disease-state contraindications, and a mandated 30 min post-procedure monitoring period for the agents Optison and Definity. These additional warnings were prompted by reports of cardiopulmonary reactions that were temporally related but were not clearly attributable to these UCAs. Subsequent published reports over the following months established not only the safety but also the improved efficacy of clinical ultrasound applications with UCAs. The FDA consequently updated the product labeling in June 2008 and reduced contraindications, although it continued to monitor select patients. In addition, a post-marketing program was proposed to the sponsors for a series of safety studies to further assess the risk of UCAs. Then in October 2011, the FDA leadership further downgraded the warnings after hearing the results of the post-marketing data, which revealed continued safety and improved efficacy. The present review focuses on the use of UCAs in today's clinical practice, including the approved indications, a variety of off-label uses, and the most recent data, which affirms the safety and efficacy of UCAs.

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).

Neovascularization of the arterial walls by adventitial vasa vasorum appears to participate in the process of atherosclerosis progression and destabilization. Although the biological mechanisms associated with plaque instability are still unclear, the uncontrolled formation of intraplaque neovessels appears to contribute to the development of complex atheromatous lesions. Recent reports have described the use of several ultrasound-based techniques for the real-time detection of intraplaque neovascularization. Preliminary studies in animal models have shown that the detection and characterization of adventitial neovascularization are technically feasible. The further development of these imaging techniques relies on the successful implementation of contrast microspheres capable of enhancing microvascular structures. These contrast agents serve as surrogate red blood cells and perform acoustically as true intravascular tracers providing, in real-time, the amount and distribution of neovessels within atherosclerotic lesions. Several ultrasound-based techniques are under development for the detection of adventitial vasa vasorum in the carotid and coronary vascular territories. Although still in early validation phases, these techniques might permit the early diagnosis and stratification of subclinical atherosclerosis, thus permitting aggressive preventive therapy. In the near future, innovative contrast agents using specific ligands are likely to expand the diagnostic and therapeutic possibilities of these emerging imaging techniques.

Introduction:Elevated soluble urokinase type plasminogen activator (suPAR) is a risk factor for renal and cardiovascular (CV) diseases in the general population.Hypothesis:We evaluated associations between suPAR and markers of subclinical cardiotoxicity in breast cancer (BCa) patients receiving standard (std) dose doxorubicin (DOX) therapy.Methods:We conducted a prospective study of patients at Rush University Medical Center who received std (≤240 mg/m2, 4 cycles) DOX-based chemotherapy for BCa between January 2017 and May 2019. We used mixed effects linear regression models to evaluate associations between suPAR and global longitudinal strain (GLS), NT-proBNP, troponin-I, and hsCRP at baseline, cycle 2 and 4 of DOX, and 3, 6, and 12 months post-DOX treatment with adjustment for baseline demographics, CV risk factors, and CV medications.Results:Of the 37 women in our study (age 47±9.3 years, 60% White, 60% left-sided BCa, and 86% adjuvant radiation therapy), the median baseline suPAR was normal at 1.83 (1.31, 3.68) ng/dL. No woman experienced clinically significant cardiotoxicity during treatment (>10% decrease in LVEF to <50%). Baseline GLS was normal (-20.2±2.3%) and the mean change in GLS following DOX therapy was +1.1%. Neither baseline suPAR nor suPAR levels during treatment were associated with GLS, NT-proBNP, hsCRP, and troponin-I (all p<0.05). Surrogate biomarkers of cardiotoxicity such as troponin-I and hsCRP were not associated with GLS (p<0.05) while NT-proBNP was negatively associated with GLS with marginal significance (p=0.04).Conclusions:In patients receiving std DOX treatment for BCa ± radiation therapy, there was minimal subclinical cardiotoxicity as evidenced by minimal changes in GLS and lack of associations between cardiac biomarkers and GLS. Furthermore, suPAR was not associated with any of these markers at this std DOX dose for BCa. A normal baseline suPAR level may be associated with low risk for DOX-associated cardiotoxicity.

Background:Optimal myocardial protection during cardiac surgery with ischemic arrest is predicated on among other variables, homogeneous cardioplegia distribution. Contrast echocardiography has been shown to provide information regarding the intramyocardial distribution of cardioplegia solution. To test the hypothesis that information regarding cardioplegia distribution derived from contrast echocardiography may be associated with immediate clinical outcome after cardiac surgery, data from 21 patients were examined retrospectively.

Recently, there has been a resurgence of interest in the use of contrast-enhanced echocardiography as a means of noninvasively assessing myocardial perfusion. However, if injections of echocardiographic contrast agents are to be used for this purpose it is essential that they are not intrinsically toxic to the heart. In this study, the left ventricular end-systolic wall stress—rate-corrected velocity of fiber shortening relation, a load independent index of contractility, was studied in nine dogs. Two-dimensional and targeted M-mode echocardiographic as well as central aortic pressure tracings were made during echocardiographically gated, pressure- and volume-controlled aortic root injections of nonsonicated and sonicated Renografin-76, saline and dextrose 70% (n = 6), and sonicated and hand-agitated Renografin-76/saline mixture (n = 5). Two of nine dogs received all agents. Off-line computer videodensitometric analysis documented myocardial perfusion. In all cases, data were obtained at control and 5 and 15 seconds after injection. Additional data were collected at 25 seconds after injection for the Renografin-76/saline mixture.

This article describes the production, analysis, and reproducibility of forming microbubbles for contrast ultrasound imaging. The sonication method used to generate microbubbles was tested by four independent observers, and a subsequent laser particle counter analysis of microbubble size and concentration determined the reproducibility of the method. The results indicated that the mean bubble size was 3.3 ± 1.2 µm for the entire group, based on three trials of each of the four participants. The characteristics of the bubble size of the microbubbles between observers were assessed with a Poisson distribution with the reproducibility based on the sample mean for each observer's trials. Standardization and calibration of the laser particle counter was accomplished with commercially available latex spheres, sonicated albumin microspheres, and a Coulter counter analysis. Our results indicate that the sonication technique generates small microbubbles with a reproducible uniform size distribution. The method of microbubble production is reproducible and can be widely applied for use in contrast echocardiographic perfusion imaging of tissue in a variety of research and clinical studies. (J AM Soc ECHO 1989;2:125-31.)

Contrast echocardiography has been used for qualitative assessment of cardiac function, and its potential for quantitative assessment of blood flow is being explored. With the development of an ultrasound contrast agent capable of passage through the microcirculation, a mathematical model based on classic dye dilution theory, and a digital ultrasound acquisition system, absolute quantitation of myocardial perfusion may be feasible. This study validates the mathematical model in a simple in vitro tube system. Flow was delivered at variable rates through an in vitro tube system while a longitudinal section was imaged with a modified commercial ultrasound scanner. Albunex contrast agent was injected, and videointensity data were captured and analyzed off line. Time-intensity curves were generated, and flow was calculated by use of a mathematical model derived from classic dye dilution mathematics. For 39 different flow rates, ranging for 9.2 to 110 mi l seconds, a correlation coefficient of r= 0.928 (p< 0.001) with a slope of 0.97 was calculated. We conclude that (1) contrast ultrasonography is capable of quantitative determination of flow in an in vitro system, and (2) a mathematical model based on dye dilution theory can be used to calculate flow with accuracy and precision.

Contrast ultrasonography may be used to assess regional tissue perfusion. The purpose of this study was to evaluate the safety and efficacy of a new; commercially prepared ultrasound contrast agent (Albunex) in dogs. The injections were administered from peripheral intravenous (IV), right atrial (RA), and pulmonary artery (PA) sites. Acute pulmonary hemodynamic and gas exchange effects of low-dose (0.5, 1.0, 2.0 ml) Phase I injections, and high-dose (2.0, 5.0, 10, 20 ml) Phase II injections of Albunex were evaluated in nine dogs. Immediately before and after each injection, pulmonary artery pressure (PAP) and oxygen tension (Po2) were determined. In addition, left ventricular cavity opacification was assessed visually and by videodensitometric off-line analysis. Visual assessment was performed by four blinded observers who graded on a scale of 0 to 3 (0 = no contrast enhancement of the left ventricular (IV) cavity; 1 = weak or suboptimal contrast enhancement; 2 = optimal or excellent contrast enhancement; and 3 = attenuation of the ultrasound signal following a contrast injection). Peak pixel intensity was also determined with videodensitometric analysis. Results showed that significant changes in PAP or Po2 were not noted after Albunex injections, regardless of injection site or dose range. The average change in PAP after Albunex injection was 1.0 mm Hg ± 1.2 mm Hg (NS), and the average change in Po2 after Albunex injections was 6.2 mm Hg ± 6.7 mm Hg (NS). The left ventricular cavity peak pixel intensity was dependent on both injection site (PA = RA > IV) and dose range (2.0 = 1.0 > 0.5). The visually assessed scores for IV cavity opacification after different sites of injection were IV = 1.5 ± 0.69, RA = 1.9 ± 0.57, and PA = 2.2 ± 0.73; and after different doses of injection were 0.5 ml = 1.5 ± 0.71, 1.0 ml = 1.9 ± 0.63, and 2.0 ml = 2.2 ± 0.59.

Assessment of viable myocardium before and after interventional therapy has become a critical issue in modern cardiology. This report describes a new contrast echocardiographic technique using conventional two-dimensional imaging during direct intracoronary injections of small volumes (1.5 to 2.0 cc) of sonicated Ren-ografin-76. Contrast echocardiography was performed before and after coronary angioplasty in seven patients with single vessel coronary artery disease. Before angioplasty a contrast (that is, perfusion) defect was noted in all seven patients. This defect correlated with the anatomic distribution of the epicardial coronary stenosis. After angioplasty the mean gradient across the ste- notic lesion decreased from 52 ± 11 to 13 ± 14 mm Hg (p < 0.01) in association with a fall in the mean diameter of the lesion from 84 ± 8 to 29 ± 13% (p < 0.001). Increased myocardial perfusion to the area of “contrast defect” was demonstrated in only five of the seven patients, despite hemodynamically and angiographically successful angioplasty. Thus, contrast echocardiographic techniques performed during interventional therapy and used in conjunction with standard coronary angiographic procedures may provide additional physiologic information regarding regional myocardial perfusion after attempts at revascularization.

To facilitate the passage of echo contrast agents through the microcirculation and the echocardiographic study of myocardial perfusion, ultrasonic energy (sonication) was employed to produce contrast agents consisting of relatively uniform, stable and small (< 10 μ diameter) gaseous microbubbles suspended in liquid solutions. The size and persistence of the microbubbles was verified by light microscopy and an in vitro system were employed for comparative assessment of peak echo amplitude and echo persistence characteristics of various contrast agents. The study indicated that although a variety of hand-agitated and sonicated contrast agents provided satisfactory echo intensities, sonication was clearly superior to the hand-agitation method, because sonication produced smaller, more uniform and more stable microbubbles that may be suitable for myocardial contrast echocardiography.

A mechanism proposed to contribute to the antianginal effect of nitroglycerin is a redistribution of coronary blood flow to the subendocardium. Contrast echocardiography combines ultrasound with echogenic contrast agents to assess regional myocardial perfusion. This study aims to assess the effect of nitroglycerin on myocardial transmural perfusion with contrast echocardiography in humans. Nine patients scheduled for coronary angiography received 300 μg intracoronary nitroglycerin. Contrast echocardiographic studies were performed before and immediately after the administration of intracoronary nitroglycerin. Videodensitometric analysis was performed off-line to measure subendocardial and subepicardial opacification. Subendocardial opafication greater than subepicardial opacification increased from six of 13 patients before nitroglycerin administration to 11 of 13 after nitroglycerin administration (p< 0.05). Similarly, these observations increased from nine of 13 patients to 13 of 13 after nitroglycerin administration during diastole (p<0.05). Contrast echocardiography demonstrates increased subendocardial perfusion after the administration of nitroglycerin in these patients. (J Am Soc Echocardiogr 1997;10:210-14.)

Myocardial contrast echocardiography has been found to be a safe and useful technique for evaluating relative changes in myocardial perfusion and delineating areas at risk. Although earlier contrast agents required direct delivery into the coronary arteries or aortic root, a new echocardiographic contrast agent, sonicated albumin microspheres (Albunex), has been found to cross the pulmonary circulation in experimental models.

The potential for the use of contrast echocardiography to study myocardial perfusion has generated efforts to develop standardized echo contrast agents. The two methods used in this laboratory to generate microbubbles in solutions serving as contrast agents included the widely used hand-agitation method and the newer ultrasonic microcavitation (sonication) method. The latter has been demonstrated to generate smaller and more uniform microbubbles in an in vitro system.

In humans, the physiologic relation between myocardial blood flow and epicardial coronary artery anatomy remains poorly defined. With the recent development of sonicated microbubble contrast agents, it is now possible to use contrast echocardiography to assess myocardial perfusion and to correlate blood flow with angiographically identified coronary artery anatomy. The purpose of the current study was to determine myocardial perfusion patterns in patients without significant coronary artery disease. These results may be used as a reference to analyze myocardial blood flow in patients with coronary artery disease.

Objectives. This study sought to compare the impact of primary coronary angioplasty and thrombolytic therapy for acute myocardial infarction (AMI) on 1-month infarct size and microvascular perfusion.

Introduction:Soluble urokinase-type plasminogen activator receptor (suPAR) is a marker of chronic immune activation and a strong predictor of cardiovascular outcomes, including heart failure. Determining if suPAR levels are affected by cardiotoxic chemotherapy is the first step towards evaluating its potential usefulness in predicting the risk of cardiotoxicity.Methods:We measured serum suPAR, troponin-I, NT-proBNP, and high-sensitivity C-reactive protein (hs-CRP) in 23 adult women <65 years of age (mean age 49 years, 30% African American), without baseline cardiac history and receiving 4 cycles of doxorubicin (DOX) for newly diagnosed ER/PR positive, HER2 negative, non-metastatic breast cancer. Biomarkers were assessed prior to, post DOX cycle #2, cycle #4 and 3, 6, 12 months post-DOX. Speckle tracking echo was performed concurrently for global longitudinal strain (GLS) analysis. We used mixed modeling for repeated measures to examine the change in biomarkers and GLS.Results:Pre-treatment levels of suPAR was 2.76 (2.3 -2.7 ng/mL), NT-proBNP: 30.5 (14.7 -90.1 pg/mL), hs-CRP: 3.5 (1.5 -10.1 mg/L ), troponin: <0.01 ng/mL and mean GLS: -20%. Post DOX cycle #4, median suPAR and NT-proBNP levels were 22% and 310% higher than baseline respectively (p<0.01), while there was no significant change in hs-CRP, troponin-I or GLS. At 6 months post-DOX, suPAR returned to baseline levels, while NT-proBNP remained elevated (p<0.01). By median follow-up of 14 months, none of the subjects showed clinical or echocardiographic signs of cardiotoxicity.Conclusion:Serum suPAR and NT-proBNP levels increased in response to DOX treatment in breast cancer patients in the absence of significant changes in GLS or clinical signs of cardiotoxicity. NT-proBNP is a proven marker of cardiotoxicity; however suPAR levels correlated with clinically absent signs of cardiotoxicity, and may serve as a promising novel biomarker for subclinical chemotherapy-related cardiotoxicity.