Ultrasound enhancing agents in cardiovascular imaging: expanding horizons beyond coronary arteries.

From its inception as a two-dimensional snapshot of the beating heart, echocardiography has become an indelible part of cardiovascular diagnostics. The integration of ultrasound enhancing agents (UEAs) marks a pivotal transition, enhancing its diagnostic acumen beyond myocardial perfusion. These agents have refined echocardiography's capacity to visualize complex cardiac anatomy and pathology with unprecedented clarity, especially in non-coronary artery disease contexts. UEAs aid in detailed assessments of myocardial viability, endocardial border delineation in left ventricular opacification, and identification of intracardiac masses. Recent innovations in UEAs, accompanied by advancements in echocardiographic technology, offer clinicians a more nuanced view of cardiac function and blood flow dynamics. This review explores recent developments in these applications and future contemplated studies.

Validation of administrative claims to identify ultrasound enhancing agent use.

BACKGROUND: Ultrasound enhancing agents (UEAs) are an invaluable adjunct to stress and transthoracic echocardiography (STE) to improve left ventricular visualization. Despite multiple single center studies evaluating UEA use, investigation into the rates, sources of variation, and outcomes of UEA use on a national level in the United States (US) has been limited by lack of validation of UEA codes for claims analyses. METHODS: We conducted a retrospective cross-sectional study, 2019-2022, using linked multicenter electronic medical record (EMR) data from > 30 health systems linked to all-payor claims data representing > 90% of the US population. Individuals receiving STE in both EMR and claims data on the same day during the study window were included. UEA receipt as identified by presence of a Current Procedural Terminology (CPT) or National Drug Code (NDC) for UEA use within 1-day of the index STE event. We evaluated the performance of claims to identify UEA use, using EMR data as the gold standard, stratified by inpatient and outpatient status. RESULTS: Amongst 54,525 individuals receiving STE in both EMR and claims data, 12,853 (23.6%) had a UEA claim in EMR, 10,461 (19.2%) had a UEA claim in claims, and 9140 (16.8%) had a UEA claim in both within the 1-day window. The sensitivity, specificity, accuracy, positive, and negative predictive values for UEA claims were 71.1%, 96.8%, 90.8%, 87.4%. and 91.6% respectively. However, amongst inpatients, the sensitivity of UEA claims was substantially lower (6.8%) compared to outpatients (79.7%). CONCLUSIONS: While the overall accuracy of claims to identify UEA use was high, there was substantial under-capture of UEA use by claims amongst inpatients. These results call into question published rates of UEA use amongst inpatients in studies using administrative claims, and highlight ongoing need to improve inpatient coding for UEA use.

Anaphylaxis to Lumason Contrast Agent in Echocardiography after Immune Sensitization: A Case Report and Literature Review.

With the continued evolution of echocardiography techniques, novel contrast agents have been introduced to aid in evaluating cardiac structure and function. Lumason is an FDA-approved ultrasound-enhancing agent made of Sulfur hexafluoride lipid-type A microspheres. We report a case of Lumason-induced immune sensitization and subsequent anaphylaxis on re-exposure in a middle-aged male patient presenting with symptoms concerning for a cerebrovascular accident. The patient was successfully treated with steroids and antihistamines. Providers, including physicians, echocardiography technicians, and mid-level providers should be aware of and be prepared to respond to the possibility of anaphylaxis to contrast-enhancing agents used in echocardiography.

The diagnostic accuracy of contrast echocardiography in patients with suspected cardiac masses: A preliminary multicenter, cross-sectional study.

Background: To evaluate the diagnostic accuracy of contrast echocardiography (CE) in patients with suspected cardiac masses. Methods: A multicenter, prospective study involving 108 consecutive patients with suspected cardiac masses based on transthoracic echocardiography performed between November 2019 and December 2020 was carried out. CE examinations were performed in all patients. The echocardiographic diagnosis was established according to the qualitative (echogenicity, boundary, morphology of the base, mass perfusion, pericardial effusion, and motility) and quantitative (area of the masses and peak intensity ratio of the masses and adjacent myocardium A1/A2) evaluations. Results: Final confirmed diagnoses were as follows: no cardiac mass (n = 3), pseudomass (n = 3), thrombus (n = 36), benign tumor (n = 30), and malignant tumor (n = 36). ROC analysis revealed the optimal A1/A2 with cutoff value of 0.295 for a cardiac tumor from a thrombus, with AUC, sensitivity, specificity, PPV, and NPV of 0.958 (95% confidence interval (CI): 0.899-0.988), 100, 91.7, 95.7, and 100%, respectively. CE was able to distinguish malignant from benign tumors with an AUC of 0.953 (95% CI: 0.870-0.990). Multivariate logistic regression analysis revealed that tumor area, base, and A1/A2 were associated with the risk of malignant tumor (OR = 1.003, 95% CI: 1.00003-1.005; OR = 22.64, 95% CI: 1.30-395.21; OR = 165.39, 95% CI: 4.68-5,850.94, respectively). When using A1/A2 > 1.28 as the only diagnostic criterion to identify the malignant tumor, AUC, sensitivity, specificity, PPV, and NPV were 0.886 (95% CI: 0.784-0.951), 80.6, 96.7, 96.7, and 80.7%, respectively. Conclusion: CE has the potential to accurately differentiate cardiac masses by combining qualitative and quantitative analyses. However, more studies with a large sample size should be conducted to further confirm these findings. Clinical trial registration: http://www.chictr.org.cn/, identifier: ChiCTR1900026809.

Established and emerging roles for ultrasound enhancing agents (contrast echocardiography).

The ability to opacify the left ventricle and delineate the endocardium after intravenous injection of microbubble ultrasound enhancing agents is of established value to quantify volumes and function in suboptimal unenhanced images, particularly in stress echocardiograms. However, applications other than quantitation of left ventricle structure and function exist for contrast enhanced left ventricular opacification. Contrast agents enable recording of Doppler velocity signals in patients with poor ultrasound transmission, providing estimates of aortic stenosis gradient and pulmonary artery pressures. Contrast echo is of value in detecting apical hypertrophic cardiomyopathy and accompanying apical aneurysms. Most importantly, ultrasound enhancing agents can identify apical and left atrial masses when they cannot be visualized in unenhanced images, and can distinguish thrombi from tumors by visualizing the vascularity inherent in tumors. Contrast agents distinguish trabecular from compacted myocardium in noncompaction syndrome, and hypertrabeculation with other abnormal conditions. A major potential application of ultrasound enhancing agents is myocardial opacification, which can assist in identifying nonviable myocardium. Also, the delayed reappearance of myocardial perfusion after microbubble destruction identifies impaired contrary flow and can diagnose coronary stenosis. Innovative applications of ultrasound contrast agents currently under investigation, include visualizing the vaso vasorum to identify plaques and assess their vulnerability, and theranostic agents to deliver drugs and biologists and to assist in sonothrombolysis. It is anticipated that the role of ultrasound contrast agents will continue to increase in the future.

Assessment and validation of a novel fast fully automated artificial intelligence left ventricular ejection fraction quantification software.

BACKGROUND: Quantification of left ventricular ejection fraction (LVEF) by transthoracic echocardiography (TTE) is operator-dependent, time-consuming, and error-prone. LVivoEF by DIA is a new artificial intelligence (AI) software, which displays the tracking of endocardial borders and rapidly quantifies LVEF. We sought to assess the accuracy of LVivoEF compared to cardiac magnetic resonance imaging (cMRI) as the reference standard and to compare LVivoEF to the standard-of-care physician-measured LVEF (MD-EF) including studies with ultrasound enhancing agents (UEAs). METHODS: In 273 consecutive patients, we compared MD-EF and AI-derived LVEF to cMRI. AI-derived LVEF was obtained from a non-UEA four-chamber view without manual correction. Thirty-one patients were excluded: 25 had interval interventions or incomplete TTE or cMRI studies and six had uninterpretable non-UEA apical views. RESULTS: In the 242 subjects, the correlation between AI and cMRI was r = .890, similar to MD-EF and cMRI with r = .891 (p = 0.48). Of the 126 studies performed with UEAs, the correlation of AI using the unenhanced four-chamber view was r = .89, similar to MD-EF with r = .90. In the 116 unenhanced studies, AI correlation was r = .87, similar to MD-EF with r = .84. From Bland-Altman analysis, LVivoEF underreported the LVEF with a bias of 3.63 ± 7.40% EF points compared to cMRI while MD-EF to cMRI had a bias of .33 ± 7.52% (p = 0.80). CONCLUSIONS: Compared to cMRI, LVivoEF can accurately quantify LVEF from a standard apical four-chamber view without manual correction. Thus, LVivoEF has the ability to improve and expedite LVEF quantification.

Echocardiography in the time of Covid-19: Ultrasound enhancing agents save time and augment diagnostic information.

BACKGROUND: There are currently no clear guidelines regarding the use of ultrasound enhancing agents (UEAs) with transthoracic echocardiography (TTE) for patients hospitalized with Covid-19. We investigated whether the performance of TTE with UEAs provides more diagnostic information and allows for shorter acquisition time compared to unenhanced TTE imaging in this patient population. METHODS: We analyzed the TTEs of 107 hospitalized Covid-19 patients between April and June 2020 who were administered UEAs (Definity®, Lantheus). The time to acquire images with and without UEAs was calculated. A level III echocardiographer determined if new, clinically significant findings were visualized with the addition of UEAs. RESULTS: There was a mean of 11.84±3.59 UEA cineloops/study vs 20.74±8.10 non-UEA cineloops/study (p < 0.0001). Mean time to acquire UEA cineloop images was 72.28±28.18 s/study compared to 188.07±86.04 s/study for non-UEA cineloop images (p < 0.0001). Forty-eight patients (45%) had at least one new finding on UEA imaging, with a total of 62 new findings seen. New information gained with UEAs was more likely to be found in patients with acute respiratory distress syndrome (21 vs 9, p < 0.001) and in those on mechanical ventilation (21 vs 15, p = 0.046). CONCLUSIONS: TTE with UEAs required less time and fewer cineloop images compared to non-UEA imaging in patients hospitalized with Covid-19. Additionally, Covid-19 patients with severe respiratory disease benefited most with regard to new diagnostic information. Health care personnel should consider early use of UEAs in select hospitalized Covid-19 patients in order to reduce exposure and optimize diagnostic yield.

Microbubble Enhanced Echocardiography in Current Cardiology Practice.

Contrast-enhanced ultrasound imaging is a radiation-free clinical diagnostic tool that uses biocompatible contrast agents to enhance ultrasound signal, in order to improve image clarity and diagnostic performance. Ultrasound enhancing agents (UEA), which are usually gas microbubbles, are administered intravenously either by bolus injection or continuous infusion. UEA increase the accuracy and reliability of echocardiography, leading to changes in treatment, improving patient outcomes and lowering overall health care costs. In this review we describe: (1) the current clinical applications of ultrasound enhancing agents in echocardiography, with a brief review of the evidence underlying each of these applications; (2) emerging diagnostic and therapeutic applications of microbubble enhanced echocardiography (MEE), which rely either on the specific properties and composition of ultrasound enhancing agents or on the technical advances of clinical ultrasound systems; and (3) safety of MEE.

Identification of Need for Ultrasound Enhancing Agent Study (the IN-USE Study).

BACKGROUND: Ultrasound enhancing agents (UEAs) are routinely used to improve transthoracic echocardiographic (TTE) image quality, yet anticipation of UEA need is a barrier to their use. METHODS: Structured report data from 171,509 consecutive TTE studies in 97,515 patients who underwent TTE imaging from January 26, 2000, to September 20, 2018, were analyzed. Trends in UEA use and suboptimal image quality were examined. Among outpatients (92,291 TTE examinations, n = 56,479), the data set was randomly split into a 75% derivation sample and a 25% validation sample. Logistic regression was used to model the composite of either UEA receipt or suboptimal image quality (two or more nonvisualized segments) using only variables available at the start of the TTE examination. Model performance was tested in the validation sample. RESULTS: A total of 4,444 TTE examinations (2.6%) in 3,827 patients (3.9%) involved UEAs, and 28,468 TTE examinations (16.6%) in 21,994 patients (22.5%) were suboptimal. UEA use increased over the observation period. Among TTE studies with suboptimal image quality, UEA use was lower in women (P < .0001). Among outpatients referred for TTE imaging, older age, greater weight, and higher heart rate best predicted UEA use or suboptimal image quality. Model performance in the validation sample was excellent (C statistic = 0.74 [95% CI, 0.73-0.75]; calibration slope = 1.11 [95% CI, 1.06-1.15]). CONCLUSIONS: In this large, single-center, retrospective study, UEA use remained substantially below rates of suboptimal image quality, despite increases over time. Among outpatients, a simple prediction rule using three routinely collected variables available before TTE image acquisition predicted potential benefit from UEAs with high accuracy. If confirmed in other cohorts, this rule may be used to identify patients who may benefit from intravenous placement for UEA administration before TTE image acquisition, thus potentially improving work-flow efficiency.

Differentiating spontaneous echo contrast, sludge, and thrombus in the left atrial appendage: Can ultrasound enhancing agents help?

The accurate identification of thrombus in the left atrial appendage with transesophageal echocardiogram (TEE) in patients with atrial fibrillation (AF) before cardioversion is essential. Most of these patients have some grade of spontaneous echo contrast (SEC). Severe SEC is often called "sludge," and its prognosis and treatment are still controversial. Current guidelines suggest the use of ultrasound enhancing agents (UEAs) when significant SEC is present. However, little is known about the utility of the UEAs in the differentiation between sludge and less severe SEC.

Contrast-Enhanced Transrectal Ultrasound in Focal Therapy for Prostate Cancer.

PURPOSE OF REVIEW: Contrast-enhanced transrectal ultrasound (CeTRUS) is an emerging imaging technique in prostate cancer (PCa) diagnosis and treatment. We review the utility and implications of CeTRUS in PCa focal therapy (FT). RECENT FINDINGS: CeTRUS utilizes intravenous injection of ultrasound-enhancing agents followed by high-resolution ultrasound to evaluate tissue microvasculature and differentiate between benign tissue and PCa, with the latter demonstrating increased enhancement. The potential utility of CeTRUS in FT for PCa extends to pre-, intra- and post-operative settings. CeTRUS may detect PCa, facilitate targeted biopsy and aid surgical planning prior to FT. During FT, the treated area can be visualized as a well-demarcated non-enhancing zone and continuous real-time assessment allows immediate re-treatment if necessary. Following FT, the changes on CeTRUS are immediate and consistent, thus facilitating repeat imaging for comparison during follow-up. Areas suspicious for recurrence may be detected and target-biopsied. Enhancement can be quantified using time-intensity curves allowing objective assessment and comparison. Based on encouraging early outcomes, CeTRUS may become an alternative imaging modality in prostate cancer FT. Further study with larger cohorts and longer follow-up are needed.