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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses the use of contrast-enhanced ultrasound (CEUS) to assess patient's risk for atherosclerotic disease. It notes the cost effectiveness of CEUS in the context of gastrointestinal imaging, as well as its potential of depicting two surrogate markers of atheroslerosis such as adventitial vasa vasorum (VV) and intraplaque neovascularization. It also cites the critical role of noninvasive diagnosis of surrogate markers to early recognize unstable lesions and identify individuals who are at higher risk of future cardio- and cerebrovascular complications. Furthermore, it indicates the significant effect of the imaging procedure on the management asymptomatic patients with carotid lesions and patients with lower degree of carotid stenosis.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 43weeks 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. [ABSTRACT FROM AUTHOR]

The article traces the evolution of contrast enhanced ultrasound imaging (CEUS). It provides a background of the origins of the development of ultrasound contrast agents for diagnostic applications. It outlines the parameters defining the role of CEUS in the non-invasive diagnostic imaging field, including real-time processing, established user base, portability and economy. It discusses the application of CEUS in the visualization of left ventricular opacification.

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. [ABSTRACT FROM AUTHOR]

We evaluated correlates of coronary atherosclerosis, measured by coronary artery calcium, in a racially diverse group of male and female subjects with type 2 diabetes. Age, systolic blood pressure, sex, and race/ethnicity were significant determinants of coronary artery calcium. Among lipoproteins, cholesterol level contained in a particle excluded from direct measures of LDL and HDL cholesterol (designated triglyceride-rich lipoprotein cholesterol) was most strongly linked to coronary artery calcium. Neither inflammatory markers nor metabolic factors correlated with coronary artery calcium in models adjusted for age and sex, but measures of adipose distribution did. Waist-to-hip ratio and the ratio of visceral to total abdominal tissue were positively associated with coronary artery calcium. In fully adjusted multivariate models, the relationship of adiposity measures to coronary artery calcium was no longer significant after inclusion of apolipoprotein B or triglyceride-rich lipoprotein cholesterol. Traditional risk factors and race/ethnicity remain important correlates of coronary artery calcium in a cohort at elevated risk of cardiovascular disease because of type 2 diabetes. Adiposity measures are significantly associated with coronary artery calcium score, but their importance may be largely explained by apolipoprotein B or triglyceride-rich lipoprotein cholesterol. Diabetes 56:849-855, 2007 [ABSTRACT FROM AUTHOR]

Context: Carotid artery intima-media thickness (CIMT) is a marker of coronary atherosclerosis and independently predicts cardiovascular events, which are increased in type 2 diabetes mellitus (DM). While studies of relatively short duration have suggested that thiazolidinediones such as pioglitazone might reduce progression of CIMT in persons with diabetes, the results of longer studies have been less clear.Objective: To evaluate the effect of pioglitazone vs glimepiride on changes in CIMT of the common carotid artery in patients with type 2 DM.Design, Setting, and Participants: Randomized, double-blind, comparator-controlled, multicenter trial in patients with type 2 DM conducted at 28 clinical sites in the multiracial/ethnic Chicago metropolitan area between October 2003 and May 2006. The treatment period was 72 weeks (1-week follow-up). CIMT images were captured by a single ultrasonographer at 1 center and read by a single treatment-blinded reader using automated edge-detection technology. Participants were 462 adults (mean age, 60 [SD, 8.1] years; mean body mass index, 32 [SD, 5.1]) with type 2 DM (mean duration, 7.7 [SD, 7.2] years; mean glycosylated hemoglobin [HbA1c] value, 7.4% [SD, 1.0%]), either newly diagnosed or currently treated with diet and exercise, sulfonylurea, metformin, insulin, or a combination thereof.Interventions: Pioglitazone hydrochloride (15-45 mg/d) or glimepiride (1-4 mg/d) as an active comparator.Main Outcome Measure: Absolute change from baseline to final visit in mean posterior-wall CIMT of the left and right common carotid arteries.Results: Mean change in CIMT was less with pioglitazone vs glimepiride at all time points (weeks 24, 48, 72). At week 72, the primary end point of progression of mean CIMT was less with pioglitazone vs glimepiride (-0.001 mm vs +0.012 mm, respectively; difference, -0.013 mm; 95% confidence interval, -0.024 to -0.002; P = .02). Pioglitazone also slowed progression of maximum CIMT compared with glimepiride (0.002 mm vs 0.026 mm, respectively, at 72 weeks; difference, -0.024 mm; 95% confidence interval, -0.042 to -0.006; P = .008). The beneficial effect of pioglitazone on mean CIMT was similar across prespecified subgroups based on age, sex, systolic blood pressure, duration of DM, body mass index, HbA(1c) value, and statin use.Conclusion: Over an 18-month treatment period in patients with type 2 DM, pioglitazone slowed progression of CIMT compared with glimepiride.Trial Registration: clinicaltrials.gov Identifier: NCT00225264 [ABSTRACT FROM AUTHOR]

The article presents a randomized, double-blind, controlled trial comparing the effect of pioglitazone and glimepiride on carotid artery intima-media thickness in patients with type 2 diabetes mellitus. The trial was conducted at clinical sites in the Chicago, Illinois metropolitan area. The study found that over an 18-month treatment period for patients with type 2 diabetes mellitus, pioglitazone slowed the progression of carotid artery intima-media thickness to a greater degree than glimepiride.

This review discusses the development, current applications, and therapeutic potential of ultrasound contrast agents. Microbubbles containing gases act as true, intravascular indicators, permitting a noninvasive, quantitative analysis of the spatial and temporal heterogeneity of blood flow and volumes within the microvasculature. These shelled microbubbles are near-perfect reflectors of acoustic ultrasound energy and, when injected intravenously into the bloodstream, reflect ultrasound waves within the capillaries without disrupting the local environment. Accordingly, microbubble ultrasound contrast agents are clinically useful in enhancing ultrasound images and improving the accuracy of diagnoses. More recently, ultrasound contrast agents have been used to directly visualize the vasa vasorum and neovascularization of atherosclerotic carotid artery plaques, thus suggesting a new paradigm for diagnosis and treatment of atherosclerosis. Future applications of these microscopic agents include the deliver of site-specific therapy to targeted organs in the body. Medical therapies may use these microbubbles as carriers for newer therapeutic options. [ABSTRACT FROM AUTHOR]

Previous studies have used standard B-mode ultrasound to quantify the aggregate mean intimal medial thickness (IMT) of the near and far wall of the common carotid artery (CCA). Many investigators have had difficulty in accurately evaluating the near wall IMT secondary to difficulty in discerning the vessel lumen and intima. The purpose of this study is to determine the effect of contrast enhanced ultrasound on IMT measurement when compared with non-enhanced images. Twenty-six patients who had standard carotid ultrasounds completed over a 6-month period were evaluated, with 24 imaged by the same sonographer. Five to six measurements of the near and far walls were obtained over a 1cm distance, beginning and ending 0.5cm and 1.5cm proximal to the carotid bifurcation. The measurements were made with and without the contrast agent OptisonTM (perflutren protein type-A microspheres), which was given as an IV bolus (0.5-0.7 cc). Of those imaged by the same sonographer, 40 carotid arteries were examined and a total of 867 measurements were obtained. A total of 10% of the carotid ultrasounds were restudied approximately 1 month after the initial interpretation to assess observer accuracy. The near wall CCA mean (SD) IMT was 0.075 (0.019)cm for left with contrast versus 0.067 (0.023)cm for left without contrast and 0.089 (0.024)cm for right with versus 0.071 (0.022)cm for right without, p 0.0001 both sides. For the far wall of the CCA, the mean (SD) IMT comparison was 0.075 (0.021)cm for left with versus 0.070 (0.016)cm for left without, p = 0.005, and 0.070 (0.023)cm for right with versus 0.070 (0.016)cm for right without, p = 0.68. In conclusion, contrast-enhanced IMT measurement showed a highly statistically significant difference in near carotid wall thickness determinations versus non-contrast values. The thicker measurement is in agreement with previously reported data showing that non-contrast images underestimated near wall common carotid IMT in histologic samples. [ABSTRACT FROM AUTHOR]

Left ventricular ejection fraction (LVEF) is a significant predictor of morbidity and mortality; however, the optimal noninvasive modality for the quantitative determination of LVEF is not apparent.We verified the hypothesis that the various echocardiography methods of assessing LVEF using the Method of Discs with contrast (Optison human albumin microspheres; Amersham Health, Princeton, NJ) and visual assessment of LVEF using tissue harmonics and contrast harmonics compare favorably with radionuclide angiography (RNA).In a prospective analysis, 24 consecutive patients scheduled to undergo RNA had an echocardiogram using tissue harmonics and contrast harmonics on the same day. LVEF was assessed by RNA by an experienced, blinded reader using manual determination of the region of interest. LVEF was calculated using the Method of Discs (Simpson's Rule) by a blinded sonographer. LVEF was visually estimated by two blinded readers using echocardiography with tissue harmonics and contrast harmonics on separate occasions.By linear regression analysis, LVEF determination by echocardiography with contrast using the Method of Discs correlated well with RNA (r = .835, p < .0005). Using Bland-Altman analysis, the second echocardiogram reader had excellent agreement with RNA, whereas the first reader had a mean difference of 5.25% (CI 1.3-9.2; p = .012) with visual assessment using tissue harmonics and a mean difference of 4.67% (CI 0.4-8.8; p = .031) with visual assessment using contrast harmonics compared with RNA. Thus, a small difference in agreement between RNA and echocardiographic visual estimation was noted that appeared to be primarily reader dependent.LVEF determination with echocardiography with contrast using the Method of Discs correlated well with RNA and provided agreement across a range of cardiac functions. Visual echocardiographic assessment of LVEF with both tissue harmonics and contrast harmonics correlated well with RNA, but contrast harmonics did not appear to offer an advantage over tissue harmonics alone. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to transient ischemic attack complicating agitated saline contrast in a patient with platypnea-orthodeoxia syndrome, by G. Loncar published in a previous issue of 2015.

The article focuses on a study that evaluated the effectiveness of pioglitazone (PIO) and glimepiride (GLM) on adipose tissue distribution. It states that there were changes in BMI, waist-hip ratio, and abdominal adipose tissue distribution based on the measurement made through the use of electron beam tomography. The findings indicate that the ratio of visceral to total adipose tissue volume tended to increase with GLM and decrease with PIO.

Patients with type 2 diabetes (T2D) manifest a form of dyslipidemia typified by high LDL particle concentration (PC), small LDL particle size (PS), and high triglyceride and low HDL-C levels. This diabetic dyslipidemia may contribute to the excess cardiovascular events seen in T2D. In CHICAGO, a randomized, double-blind, multicenter, 72-week study, pioglitazone (PIO) was associated with less CIMT progression compared to glimepiride (GLM) in patients with T2D (N=462). We also observed significant improvements in TG and HDL-C levels with PIO vs GLM, with no difference in LDL-C levels. Here we report the results of the lipoprotein subfraction analysis. Blood samples were obtained at baseline and weeks 24, 48, and 72 (or time of withdrawal) for determination of PC and PS of VLDL, LDL, and HDL, measured by NMR spectroscopy. At Final Visit, PIO therapy produced a significant reduction in VLDL PS due to significant decreases in large and medium VLDL PC and increases in small VLDL PC. LDL PS significantly increased due to a significant reduction in small LDL and increase in large LDL PC. HDL PS also significantly increased due to a reduction in small and an increase in large HDL PC. In aggregate, the changes in lipoprotein subfraction distribution would be predicted to produce a reduction in CVD risk with PIO vs GLM and may contribute to beneficial effects of PIO on CIMT. [ABSTRACT FROM AUTHOR]

Abstract: Recently, debate has erupted about the clinical significance of cardiovascular shunts. Several major health problems such as stroke and migraine have been associated with patent foramen ovale (PFO) with right-to-left shunt (RLS). The nature of the relationship between these syndromes and PFO is not clearly understood. Technical advances have led to more therapeutic options including device closure of PFO, hence prevention of such a PFO-related stroke has become feasible. Therefore, optimal diagnosis of PFO has become of greater clinical importance. Contrast echocardiography with non-transpulmonary contrast agents has been the cornerstone in diagnosis of PFO with RLS for over four decades. Despite being a relatively invasive procedure, transesophageal echocardiography (TEE) is considered the gold standard for detection of RLS. Several other echocardiographic techniques such as transthoracic echocardiography (TTE) with second harmonic imaging and transcranial Doppler ultrasonography (TCD) have shown increased sensitivity and specificity compared to TEE for the detection of PFO with RLS. Moreover, improvement of skills and techniques used for detection of these shunts has led to greater detection of small and large sized RLS in the echocardiographic laboratory. This review gives and overview of the echocardiographic techniques, contrast agents and manoeuvres used for detection of the major cardiovascular shunts and their clinical relevance to major health problems. [Copyright &y& Elsevier]