Mary E. Hagen

American Society of Echocardiography Consensus Statement on the Clinical Applications of Ultrasonic Contrast Agents in Echocardiography

UNLABELLED ACCREDITATION STATEMENT: The American Society of Echocardiography (ASE) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASE designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.trade mark Physicians should only claim credit commensurate with the extent of their participation in the activity. The American Registry of Diagnostic Medical Sonographers and Cardiovascular Credentialing International recognize the ASEs certificates and have agreed to honor the credit hours toward their registry requirements for sonographers. The ASE is committed to resolving all conflict-of-interest issues, and its mandate is to retain only those speakers with financial interests that can be reconciled with the goals and educational integrity of the educational program. Disclosure of faculty and commercial support sponsor relationships, if any, have been indicated. TARGET AUDIENCE This activity is designed for all cardiovascular physicians, cardiac sonographers, and nurses with a primary interest and knowledge base in the field of echocardiography; in addition, residents, researchers, clinicians, sonographers, and other medical professionals having a specific interest in contrast echocardiography may be included. OBJECTIVES Upon completing this activity, participants will be able to: 1. Demonstrate an increased knowledge of the applications for contrast echocardiography and their impact on cardiac diagnosis. 2. Differentiate the available ultrasound contrast agents and ultrasound equipment imaging features to optimize their use. 3. Recognize the indications, benefits, and safety of ultrasound contrast agents, acknowledging the recent labeling changes by the US Food and Drug Administration (FDA) regarding contrast agent use and safety information. 4. Identify specific patient populations that represent potential candidates for the use of contrast agents, to enable cost-effective clinical diagnosis. 5. Incorporate effective teamwork strategies for the implementation of contrast agents in the echocardiography laboratory and establish guidelines for contrast use. 6. Use contrast enhancement for endocardial border delineation and left ventricular opacification in rest and stress echocardiography and unique patient care environments in which echocardiographic image acquisition is frequently challenging, including intensive care units (ICUs) and emergency departments. 7. Effectively use contrast echocardiography for the diagnosis of intracardiac and extracardiac abnormalities, including the identification of complications of acute myocardial infarction. 8. Assess the common pitfalls in contrast imaging and use stepwise, guideline-based contrast equipment setup and contrast agent administration techniques to optimize image acquisition.

Safety of Contrast Agent Use During Stress Echocardiography: A 4-Year Experience From a Single-Center Cohort Study of 26,774 Patients

OBJECTIVES We evaluated the short- and long-term safety of contrast agents during stress echocardiography (SE). BACKGROUND Concerns about contrast agent safety led to revised recommendations for product use in the U.S. METHODS We studied 26,774 patients who underwent SE between November 1, 2003, and December 31, 2007. The 10,792 patients who comprised the contrast cohort received second-generation perfluorocarbon-based agents for left ventricular opacification during SE. The noncontrast cohort comprised 15,982 patients who had their first SE in the same period but without contrast agents. Short-term (< or = 72 h and < or = 30 days) and long-term (up to 4.5 years) end points were death and myocardial infarction (MI). Cox regression models were used. Immediate contrast agent-related adverse effects were also reported. RESULTS The contrast cohort had older patients (mean [SD] age, 65.8 [12.1] years vs. 62.6 [14.1] years; p < 0.001), a higher percentage of males (57.4% vs. 52.8%, p < 0.001), and higher-risk patients compared with the noncontrast cohort. In addition, dobutamine SE patients had greater cardiac risk than exercise SE patients. Abnormal SE findings in patients who received contrast agents were more frequent (32.4% vs. 27.9%, p < 0.001). The 2 cohorts had no statistical difference in the incidence of short-term events (death and MI). Within 72 h, 1 patient in the contrast cohort and 2 patients in the noncontrast cohort died (p = 0.54); 3 in the contrast cohort and 7 in the noncontrast cohort had MI (p = 0.92). Within 30 days, 37 patients (0.34%) in the contrast cohort and 57 patients (0.36%) in the noncontrast cohort died (p = 0.85); 17 patients (0.16%) in the contrast cohort and 16 patients (0.10%) in the noncontrast cohort had MI (p = 0.19). Adjusted hazard ratios were not different between cohorts for death (0.99; 95% confidence interval: 0.88 to 1.11) or MI (0.99; 95% confidence interval: 0.80 to 1.22). CONCLUSIONS The use of contrast agents during SE was not associated with an increased short-term or long-term risk of death or MI.

Microvascular Function in Takotsubo Cardiomyopathy With Contrast Echocardiography: Prospective Evaluation and Review of Literature

BACKGROUND Takotsubo cardiomyopathy (TC) mimics ST-elevation myocardial infarction without substantial angiographic stenosis. Coronary microvascular dysfunction has been proposed as a possible mechanism in TC. The aim of this study was to evaluate microvascular function in TC using real-time myocardial contrast echocardiography (MCE). METHODS Real-time MCE was performed within 24 hours of coronary angiographic diagnosis of TC. Myocardial perfusion was evaluated through qualitative and quantitative myocardial contrast echocardiographic analyses comparing normal segments with segments with dysfunctional wall motion (WM). RESULTS From January 2007 to January 2008, 11 patients received diagnoses of TC. Of these patients, 9 were prospectively enrolled (mean age, 70.9 +/- 17.5 years; 8 women). Qualitative and quantitative myocardial contrast echocardiographic analyses were feasible in 87% and 81% of segments. Overall, concordance between qualitative MCE and WM for normal versus abnormal analysis was observed in 71% of segments (kappa = 0.442, SE = 0.08). Significantly lower myocardial blood flow velocity (beta) and lower myocardial blood flow (Abeta) were detected in segments with dysfunctional WM compared with those with normal WM (beta = 0.55 +/- 0.39 vs 0.90 +/- 0.77, P = .009; Abeta = 5.31 +/- 3.92 vs 12.38 +/- 13.47, P = .002). In the discordant segments between qualitative MCE and WM, the quantitative perfusion parameters beta and Abeta were significantly lower in segments with dysfunctional WM compared with those with normal WM (beta = 0.22 +/- 0.20 vs 1.79 +/- 0.57, P = .01; Abeta = 1.90 +/- 1.1 vs 24.29 +/- 19.9, P = .02). Recovery of WM abnormalities was detected in all patients during follow-up echocardiography (mean, 60.3 +/- 66.0 days). No contrast-related side effects were reported. During mean follow-up of 5.9 +/- 4.6 months, there were no cardiac events, but 1 noncardiac death (from lung cancer) occurred. CONCLUSION TC is associated with abnormal myocardial perfusion detected with qualitative and quantitative MCE, indicative of microvascular dysfunction.

Safety of Contrast Agent Use during Stress Echocardiography in Patients with Elevated Right Ventricular Systolic Pressure: A Cohort Study

Background—Microbubble safety concerns led to changes in product recommendations for patients with pulmonary hypertension. Noninvasive estimation of right ventricular systolic pressure (RVSP) is equivalent to pulmonary artery systolic pressure in the absence of pulmonary outflow obstruction. We analyzed the short- and long-term outcomes of patients who received microbubble contrast and those who did not during stress echocardiography (SE) according to resting RVSP. Methods and Results—From November 2003 to December 2007, 26 774 patients underwent SE. RVSP (mean, 32.6±9.6 mm Hg) was measured in 16 434 patients. Of these, 6164 (37.5%) received contrast for left ventricular opacification and 10 270 (62.5%) did not. Short-term (≤72 hours and ≤30 days) and long-term (4.3 years) end points were death and myocardial infarction. Analysis was done for rest RVSP cut-points ≥35, ≥50, and ≥60 mm Hg and tricuspid regurgitant velocities ≥2.7 ms−1 and ≥3.5 ms−1. Adjusted Cox regression models were used. The contrast cohort comprised older patients (age, 67±12 versus 64±14 years; P<0.001), who were more likely to have positive SE results (35% versus 30%, P<0.001) compared with the noncontrast cohort. Using RVSP ≥50 mm Hg, there was no significant difference in short-term events between the contrast and noncontrast cohorts. For long-term events, there was no significant difference between both cohorts (adjusted hazard ratios [95% confidence intervals] for death, 1.10 [0.80 to 1.50], P=0.56; and myocardial infarction, 0.34 [0.11 to 1.03], P=0.06). Similar results were obtained at different RVSP and tricuspid regurgitant cut-points. Contrast agent-related adverse effects occurred in <1% of patients. Conclusion—RVSP had no impact on predisposition to adverse outcomes in patients undergoing contrast SE in the population studied.

Contrast Echocardiography Using Intravenous Octafluoropropane and Real-time Perfusion Imaging Predicts Functional Recovery After Acute Myocardial Infarction

Akinesia after acute myocardial infarction (MI) may be reversible, secondary to stunning, or irreversible, as a result of extensive myocyte necrosis. Distinguishing these 2 entities soon after MI is difficult, but has important clinical implications. The current study assessed the use of intravenous myocardial contrast echocardiography (MCE) in this setting. A total of 35 patients were studied 2 (+/- 1) days after an acute MI. Of these, 31 (91%) underwent myocardial revascularization. Perfusion was assessed using real-time MCE and an intravenous infusion of octafluoropropane microbubbles. Repeated echocardiograms were obtained 56 (+/- 29) days later. Normal perfusion predicted functional recovery with a positive predictive value of 66% and a negative predictive value of 81%. The accuracy of the technique was superior in myocardial segments supplied by the left anterior descending coronary artery (positive and negative predictive value: 70% and 90%, respectively). In multivariable analysis, the mean MCE perfusion score in akinetic segments was the most powerful independent predictor of functional recovery (odds ratio 8.6, P =.02). These data suggest that real-time intravenous MCE is a useful predictor of functional recovery of akinetic myocardium after acute MI.

Comparison of intravenous myocardial contrast echocardiography and low-dose dobutamine echocardiography for predicting left ventricular functional recovery following acute myocardial infarction

Akinesia after acute myocardial infarction (AMI) may be reversible or irreversible. Distinguishing these 2 entities early after AMI is difficult, but clinically important. Previous studies have shown that myocardial contrast echocardiography (MCE) and low-dose dobutamine echocardiography (DE) may both be useful in this setting. However, there are few data regarding the relative and combined value of these techniques. The aim of this study was to compare the utility of real-time intravenous MCE and low-dose DE in the early prediction of functional recovery of akinetic myocardium after AMI. Thirty-seven patients were studied 3 +/- 2 days after an AMI. Each subject underwent real-time MCE using an intravenous infusion of perflutren microbubbles. Immediately after this, low-dose DE was performed. Contrast opacification and wall motion were determined by experienced observers blinded to clinical data. Repeat echocardiograms were obtained 51 +/- 19 days later and wall motion at rest was scored by an observer blinded to clinical data. Normal contrast opacification predicted functional recovery with a positive predictive value of 63%, a negative predictive value of 73%, and an accuracy of 66%. Residual contractility during low-dose DE had a positive predictive value of 82%, a negative predictive value of 72%, and a predictive accuracy of 76%. When the 2 tests were concordant (64%), they had a positive predictive value of 81%, a negative predictive value of 85%, and a predictive accuracy of 83%. Low-dose DE was superior to intravenous MCE in the prediction of functional recovery of akinetic myocardium after AMI, but the combination of both maximizes predictive accuracy.

Assessment of Myocardial Perfusion during Adenosine Stress Using Real Time Three‐Dimensional and Two‐Dimensional Myocardial Contrast Echocardiography: Comparison with Single‐Photon Emission Computed Tomography

Objectives: To evaluate diagnostic accuracy of adenosine two‐dimensional and three‐dimensional myocardial contrast echocardiography (2D‐ and 3D‐MCE) compared with single‐photon emission computed tomography (SPECT) for assessing myocardial perfusion. Methods: From January through August 2007, patients with known or suspected CAD who were referred for SPECT underwent simultaneous adenosine 2D‐MCE and 3D‐MCE (live and full volume [FV]). Perfusion and wall motion in 17 segments in the left anterior descending, left circumflex, and right coronary artery territories were analyzed. Results: We studied 30 patients: mean (SD) age, 72.6 (8.2) years; 19 (63%) men. Perfusion by SPECT was abnormal in 13 patients (43%). When comparing MCE with SPECT, sensitivity was comparable for 2D‐MCE, 92%; live 3D‐MCE, 91%; and FV 3D‐MCE, 90%. Specificity was comparable for 2D‐MCE, 75%; live 3D‐MCE, 69%; and FV 3D‐MCE, 79%. Agreement between live 3D‐MCE and 2D‐MCE was 92% (κ[SE], 0.83 [0.17]) and between FV 3D‐MCE and 2D‐MCE, 88% (κ[SE], 0.76 [0.13]). For eight patients in whom SPECT showed reversible defects, live 3D‐MCE correctly identified defects in seven (88%), whereas FV 3D‐MCE correctly identified them in five (63%) (P = 0.57). Conclusion: Myocardial perfusion assessment is feasible by 3D‐MCE with the advantage of rapid, facile acquisition and offline image manipulation. (Echocardiography 2010;27:421‐429)

Diagnostic accuracy of contrast echocardiography during adenosine stress for detection of abnormal myocardial perfusion: a prospective comparison with technetium-99 m sestamibi single-photon emission computed tomography

Myocardial contrast echocardiography (MCE) utilizes compressible microbubbles behaving similarly to red blood cells. Destruction of microbubbles and observation of the gradual refill into the myocardium are key to evaluating perfusion using real-time MCE. We aimed to assess the feasibility and diagnostic accuracy of qualitative MCE utilizing a 17-segment model for localization of myocardial perfusion abnormalities compared with simultaneous technetium-99 m sestamibi single-photon emission computed tomography (SPECT). From July 2005 through August 2007, 97 patients with known or suspected coronary artery disease underwent simultaneous SPECT and realtime MCE during adenosine stress. Qualitative MCE and tracer uptake were analyzed visually using a 17-segment model in a blinded manner. Diagnostic accuracy and 95% confidence interval (CI) were determined. Myocardial contrast echocardiography was completed in 91 patients (age, mean [SD], 69.3 [10.9] years; body mass index, 30.0 [6.3]; 59 males [65%]). Myocardial contrast echocardiography analysis was feasible in 88 (97%) patients (261 of 264 [99%] territories; 1299 of 1497 [87%] segments). At patient level, MCE sensitivity was 88% (95% CI, 79%–94%); specificity was 85% (77%–90%). For disease detection in individual coronary territories, sensitivity and specificity were 84% (71%–92%) and 79% (72%–84%) for the left anterior descending artery; 62% (38%–80%) and 88% (83%–91%) for the left circumflex artery; and 73% (57%–82%) and 94% (89%–97%) for the right coronary artery. For MCE combined with wall-motion analysis, concordance with SPECT improved from 80% to 86%. Myocardial contrast echocardiography interobserver concordance was 81% (κ [SE], 0.611 [0.78]). Myocardial contrast echocardiography accuracy was comparable in patients classified in accordance with presence of diabetes mellitus, myocardial infarction, hypertension, or percutaneous coronary intervention. Improved MCE specificity in detecting perfusion defects was seen in patients with no history of coronary bypass graft surgery (P = 0.005). Real-time MCE with a 17-segment model for analysis has good feasibility and accuracy in evaluation of myocardial perfusion during adenosine stress.

Absolute Myocardial Blood Flow Determination Using Real Time Myocardial Contrast Echocardiography During Adenosine Stress: Comparison With Single-Photon Emission Computed Tomography

Objective: To assess the feasibility and diagnostic accuracy of real-time myocardial contrast echocardiography (MCE)-derived absolute myocardial blood flow for detection of myocardial perfusion abnormalities compared with simultaneous technetium 99 m sestamibi single-photon emission computed tomography (SPECT). Design: Prospective study. Setting: Tertiary-care medical institution. Patients: 79 patients with known or suspected coronary artery disease. Interventions: Simultaneous SPECT and real-time MCE during adenosine stress. Main outcome measures: Absolute myocardial blood flow (MBF, ml/min/g), microbubble velocity (β, min−1), and reserve values. Endpoints included sensitivity, specificity, positive likelihood ratio (LR+) or negative likelihood ratio (LR−) and area under the curve (AUC) of the receiver operating characteristic curve. Results: Reserve measurements were feasible in 975 of 1343 segments (73%); of these, 130 segments (13%) were abnormal by SPECT. MCE perfusion parameters clearly distinguished abnormal from normal segments for β reserve (1.13 (0.99) vs 2.22 (1.36), p<0.001) and MBF reserve (1.80 (2.29) vs 3.69 (2.79), p<0.001). The β reserve cut-off of 1.60 provided the following: AUC, 0.787; sensitivity, 82%; specificity, 66%; LR+, 2.40; and LR−, 0.28. The MBF reserve cut-off of 1.90 provided the following: AUC, 0.779; sensitivity, 73%; specificity, 72%; LR+, 2.69; and LR−, 0.37. MBF reserve had an AUC of 0.773 for the left anterior descending coronary artery, 0.885 for the left circumflex coronary artery and 0.739 for the right coronary artery. Conclusions: Real-time MCE-derived absolute MBF, β, and reserve values are feasible and accurate for detecting myocardial perfusion abnormalities as defined by SPECT.

A Multicenter, Prospective Study to Evaluate the Use of Contrast Stress Echocardiography in Early Menopausal Women at Risk for Coronary Artery Disease: Trial Design and Baseline Findings

AIMS This multisite prospective trial, Stress Echocardiography in Menopausal Women At Risk for Coronary Artery Disease (SMART), aimed to evaluate the prognostic value of contrast stress echocardiography (CSE), coronary artery calcification (CAC), and cardiac biomarkers for prediction of cardiovascular events after 2 and 5 years in early menopausal women experiencing chest pain symptoms or risk factors. This report describes the study design, population, and initial test results at study entry. METHODS From January 2004 through September 2007, 366 early menopausal women (age 54±5 years, Framingham risk score 6.51%±4.4 %, range 1%-27%) referred for stress echocardiography were prospectively enrolled. Image quality was enhanced with an ultrasound contrast agent. Tests for cardiac biomarkers [high-sensitivity C-reactive protein (hsCRP), atrial natriuretic protein (ANP), brain natriuretic protein (BNP), endothelin (ET-1)] and cardiac computed tomography (CT) for CAC were performed. RESULTS CSE (76% exercise, 24% dobutamine) was abnormal in 42 women (11.5%), and stress electrocardiogram (ECG) was positive in 22 women (6%). Rest BNP correlated weakly with stress wall motion score index (WMSI) (r=0.189, p<0.001). Neither hsCRP, ANP, endothelin, nor CAC correlated with stress WMSI. Predictors of abnormal CSE were body mass index (BMI), diabetes mellitus, family history of premature coronary artery disease (CAD), and positive stress ECG. Twenty-four women underwent clinically indicated coronary angiography (CA); 5 had obstructive (≥50%), 15 had nonobstructive (10%-49%), and 4 had no epicardial CAD. CONCLUSIONS The SMART trial is designed to assess the prognostic value of CSE in early menopausal women. Independent predictors of positive CSE were BMI, diabetes mellitus, family history of premature CAD, and positive stress ECG. CAC scores and biomarkers (with the exception of rest BNP) were not correlated with CSE results. We await the follow-up data.