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Contrast Echocardiography

EACVI Key Reference Library

Historical & Landmark Papers

Impact of Contrast Echocardiography on Evaluation of Ventricular Function and Clinical Management in a Large Prospective Cohort

Kurt M, Shaikh KA, Peterson L, Kurrelmeyer KM, Shah G, Nagueh SF, Fromm R, Quinones MA, Zoghbi WA.
632 patients with technically challenging echo windows, who thus received contrast agent(s), were prospectively enrolled. After contrast, the percent of uninterpretable studies decreased from 11.7% to 0.3% and technically difficult studies decreased from 86.7% to 9.8% (p< 0.0001). Before contrast, 11.6± 3.3 of 17 LV segments were seen, which improved after contrast to 16.8±1.1 (p< 0.0001). A significant impact on management was observed: additional diagnostic procedures were avoided in 32.8% of patients and drug management was altered in 10.4%, total impact (procedures avoided, change in drugs, or both) in 35.6% of patients. A cost–benefit analysis showed a significant savings using contrast ($122/patient).
Reference: J Am Coll Cardiol. 2009; 53(9); 802-10

Myocardial contrast echocardiography for distinguishing ischemic from nonischemic first-onset acute heart failure: insights into the mechanism of acute heart failure

Senior R, Janardhanan R, Jeetley P, Burden L.
This study was the first to prove the value of MCE in identifying aetiology (ischaemic vs non-ischaemic) in patients presenting for the first time with heart failure. 52 patients with acute heart failure but no prior cardiac history underwent rest and stress MCE prior to cardiac catheterisation. Sensitivity, specificity, positive and negative predictive values for MCE to detect a >50% coronary stenosis were 82%, 97%, 95% and 88% respectively.
Reference: Circulation 2005;112(11):1587-93

Comparative accuracy of real-time myocardial contrast perfusion imaging and wall motion analysis during dobutamine stress echocardiography for the diagnosis of coronary artery disease

Elhendy A, O'Leary EL, Xie F, McGrain AC, Anderson JR, Porter TR.
This was the first study to show that perfusion assessment has incremental benefit over wall motion analysis in detecting CAD. 170 patients underwent MCE during dobutamine stress echocardiography prior to coronary angiography. MCE was more sensitive than wall motion analysis for detecting CAD (>50% stenosis on angiography) at peak and intermediate stress. Overall accuracy was higher for MCE than for WMA (81% vs. 71%; p = 0.01).
Reference: J Am Coll Cardiol. 2004; 44 (11); 2185-91

Intravenous myocardial contrast echocardiography predicts recovery of dyssynergic myocardium early after acute myocardial infarction

Swinburn JM, Lahiri A & Senior R.
The first paper to show that delayed imaging (1:10) is the technique of choice for detecting myocardial viability. 96 patients with recent acute MI underwent echocardiography at baseline and 6 months later or 3 months after revascularization to determine regional function. MCE was performed at baseline using triggering intervals of 1:1 (early) and 1:10 (delayed) cardiac cycles. Delayed imaging had superior positive and negative predictive value for recovery of systolic function. The authors concluded that delayed triggered MCE can independently detect myocardial viability early after AMI and that delayed triggered imaging is superior to early triggered imaging.
Reference: J Am Coll Cardiol 2001; 38(1):19-25.

Real-time assessment of myocardial perfusion and wall motion during bicycle and treadmill exercise echocardiography: comparison with single photon emission computed tomography

Shimoni S, Zoghbi WA, Xie F, Kricsfeld D, Iskander S, Gobar L, Mikati IA, Abukhalil J, Verani MS, O’Leary, Porter TR.
One of the first studies to demonstrate the feasibility and accuracy of low-power real-time MCE using exercise stress (n=50 bicycle, n=50 treadmill) as opposed to pharmacological stress. MCE correlated well with SPECT imaging and sensitivity and specificity for detecting CAD (defined on angiography) were 75% and 81% respectively. The best diagnostic accuracy (86%) was seen when perfusion (MCE) and wall motion findings were combined.
Reference:J Am Coll Cardiol 2001; 37 (3); 741-47

Role of capillaries in determining CBF reserve: new insights using myocardial contrast echocardiography

Jayaweera AR, Wei K, Coggins M, Ping Bin J, Goodman C, Kaul S.
Landmark study which proved, for the first time, that capillaries play a crucial role in regulation of coronary blood flow (CBF). A canine model of the coronary circulation with three compartments was created (arterial, capillary, venous). In a normal state, capillaries contributed just 25% of the total myocardial vascular resistance at rest but this rose to 75% during maximal hyperaemia, despite total myocardial vascular resistance falling. In the presence of a non-critical stenosis, total myocardial vascular resistance increased during hyperaemia predominantly due to increased capillary resistance. Thus, contrary to widely held beliefs at that time, capillaries were shown to participate in CBF regulation.
Reference: Am J Physiol Heart Circ Physiol 1999; 277; H2363-H237

Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion

Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S.
Landmark study that provided proof for the physiological basis of quantification of MCE by studying bubble and ultrasound interaction. Myocardial blood flow (MBF) studied in ex-vivo and in-vivo experimental models in 21 dogs. Demonstrated that the peak video intensity (A) reflected myocardial blood volume and that the slope of the curve obtained by plotting video intensity against pulsing interval was equal to the microbubble velocity (β). The product (A x β) gives myocardial blood flow.
Reference: Circulation 1998;97(5):473-83

An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction

Sabia PJ, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S.
Regional LV systolic function was assessed before and one month after attempted angioplasty in 43 patients with recent (<5weeks) myocardial infarction (MI) resulting in an occluded infarct-related artery (IRA). It was shown that collateral-derived residual flow is common in such patients and that it can maintain viability for several weeks. Moreover, the degree of improvement of regional function after revascularisation was related to the percentage of the occluded bed perfused by collateral flow. The authors concluded that viability appears to be directly associated with the presence of collateral blood flow within the infarct bed.
Reference: N Engl J Med 1992; 327: 1825-1831

Safety and efficacy of a new transpulmonary ultrasound contrast agent: initial multicenter clinical results

Feinstein SB, Cheirif J, Ten Cate FJ, Silverman PR, Heidenreich PA, Dick C, Desir RM, Armstrong WF, Quinones MA, Shah PM
The first study in man using Albunex – sonicated albumin – contrast agent. Safety was proven, but only 63% of injections were judged to cause adequate LV opacification.
Reference: J Am Coll Cardiol 1990; 16(2):316-24

Two-dimensional contrast echocardiography: In vitro development and quantitative analysis of echo contrast agents

Feinstein SB, Ten Cate FJ, Zwehl W, Ong K, Maurer G, Tei C, et al.
Classic study that showed that ‘sonication’ of dextrose / sorbitol solutions (exposure to ultrasonic energy) produced small, uniform and stable microbubbles capable of opacifying the LV and could be used as ultrasound contrast agents.
Reference: J Am Coll Cardiol 1984;3(1):14-20

Contrast for improving LV structural & functional assessment

Safety and efficacy of commercially available ultrasound contrast agents for rest and stress echocardiography a multicenter experience

Dolan MS, Gala SS, Dodla S, Abdelmoneim SS, Xie F, Cloutier D, Bierig M, Mulvagh SL, Porter TR, Labovitz AJ.
A retrospective analysis of 42,408 patients who had baseline suboptimal images and/or underwent perfusion imaging and received contrast agents; 18,749 of these underwent stress echocardiography. Endocardial border visualization in patients with sub-optimal images given contrast resulted in comparable sensitivity (81% vs. 73%, p = NS) and diagnostic accuracy (82% vs. 77%, p = NS) for wall motion analysis compared with patients with optimal image quality. They concluded that contrast is a safe and useful diagnostic tool in the stress echocardiography laboratory.
Reference: J Am Coll Cardiol. 2009; 53(1); 32-8

A randomized cross-over study for evaluation of the effect of image optimization with contrast on the diagnostic accuracy of dobutamine echocardiography in coronary artery disease The OPTIMIZE Trial

Plana JC, Mikati IA, Dokainish H, Lakkis N, Abukhalil J, Davis R, Hetzell BC, Zoghbi WA.
In a unique randomised trial setting, 101 patients referred for DSE agreed to have the test twice within a 24hour period – once with contrast and once without. The use of a contrast agent improved the percentage of segments adequately visualized at baseline (from 72 to 95%) and more so at peak stress (67 to 96%). Interpretation of wall motion with high confidence also increased with contrast agent use from 36% to 74%. The authors concluded that during dobutamine echocardiography, contrast agent administration improves endocardial visualization at rest and more so during stress, leading to a higher confidence of interpretation and greater accuracy in evaluating CAD.
Reference: JACC Cardiovasc Imaging. 2008 Mar; 1(2); 145-52

Analysis of regional left ventricular function by cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography

Hoffmann R, von Bardeleben S, Kasprzak J, Borges AC , ten Cate F, Firschke C, Lafitte S, Al-Saadi N, Kuntz-Hehner S, Horstick G, Greis C, Engelhardt M, Vanoverschelde JL & Becher H.
56 patients had LV regional systolic function assessed using several imaging techniques. The best inter-observer agreement was found with contrast echocardiography (ĸ = 0.77) whereas it was significantly lower for ventriculography (ĸ = 0.56) and CMR (ĸ = 0.43). Accuracy to detect regional abnormalities, as defined by an expert panel, was highest for contrast echocardiography.
Reference: J Am Coll Cardiol (2006); 47(1); 121-28

Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography

Hoffmann R, von Bardeleben S, ten Cate F, Borges AC, Kasprzak J, Firschke C, Lafitte S, Al-Saadi N, Kuntz-Hehner S, Engelhardt M, Becher H & Vanoverschelde JL.
55 patients had LV systolic function assessed using several imaging techniques and the results were read by 3 experts (1 on site and 2 off site). Unenhanced echocardiography underestimated ejection fraction (EF) and had only moderate correlation with CMR and ventriculography. Contrast-enhanced echo provided a much more accurate EF with superior correlation with CMR. The inter-observer variability (measured by intra-class coefficient) was highest for contrast echo (0.91), followed by CMR (0.86), cineventriculography (0.80) and unenhanced echo (0.79).
Reference: Eur Heart J (2005); 26; 607-16

Accurate and reproducible measurement of left ventricular volume and ejection fraction by contrast echocardiography: a comparison with magnetic resonance imaging

Malm S, Frigstad S, Sagberg E, Larsson H, Skjaerpe T.
A Norwegian prospective study in which 110 patients underwent unenhanced 2D echocardiography, contrast-enhanced 2D-echo and cardiac MRI (1.5T). EF and LV volumes were significantly underestimated by unenhanced echo and accuracy of all parameters were significantly improved by use of contrast, including inter-observer and intra-observer variability.
Reference: J Am Coll Cardiol. 2004; 44(5); 1030-5

MCE for detection of myocardial ischaemia

Contrast stress echocardiography predicts hard cardiac events in patients with suspected acute coronary syndrome but non-diagnostic electrocardiogram and negative 12-hr troponin.

Gaibazzi N, Squeri A, Reverberi C, Molinaro S, Lorenzoni V, Sartorio D, Senior R.
This is the first study to demonstrate the incremental benefit of myocardial perfusion assessment in this acute patient population. 545 patients referred from the Emergency Department underwent dipyridamole-atropine stress echocardiography and were followed-up for 12months thereafter. Abnormal MCE was the single best predictor of adverse cardiac events, both hard events and a composite end-point including hospitalisation for recurrent angina. The inclusion of MCE results significantly improved the multivariate model, even with inclusion of wall motion data.
Reference: J Am Soc Echo (2011); 24(12); 1333-41

Myocardial contrast echocardiography for the detection of coronary artery stenosis: a prospective multicenter study in comparison with single-photon emission computed tomography

Jeetley P, Hickman M, Kamp O, Lang RM, Thomas JD, Vannan MA, et al.
123 patients clinically scheduled to undergo coronary angiography underwent triggered intermediate mechanical index (0.5) MCE and SPECT at rest and after vasodilator stress. 78% patients had ≥1 coronary stenosis >50%. MCE and SPECT had similar sensitivity (84% vs 82%) and specificity (56% vs 52%) for detection of CAD in this high-risk cohort.
Reference: J Am Coll Cardiol 2006;47(1):141-5

Prognostic Value of Dobutamine Stress Myocardial Contrast Perfusion Echocardiography

Tsutsui JM, Elhendy A, Anderson JR, Xie F, McGrain AC & Porter TR.
This key paper involved a retrospective analysis of 788 patients who had undergone MCE during stress echocardiography with dobutamine. For the first time, incremental prognostic value over clinical variables and, crucially, wall motion was proven – patients with normal perfusion had better outcomes (median follow-up period 20months) than those with normal wall motion.
Reference: Circulation. 2005; 112(10); 1444-50

Usefulness of myocardial contrast echocardiography derived coronary flow reserve to accurately determine severity of left anterior descending coronary artery stenosis

Hickman M, Jeetley P, Senior R.
This study in 35 patients proved that MCE can detect not just the presence but also the severity of CAD in patients with LAD coronary stenosis. Quantitative MCE was performed up to 4 weeks prior to coronary angiography. Patients were divided into four groups based on severity of LAD stenosis (<50%, 50-75%, 75-99% and 100% occlusion). MCE-derived coronary flow reserve was significantly different between each of the four groups and accurately predicted severity of disease.
Reference: Am J Cardiol 2004;93(9):1159-62

Assessment of the physiologic significance of coronary disease with dipyridamole real-time myocardial contrast echocardiography. Comparison with technetium-99m sestamibi single-photon emission computed tomography and quantitative coronary angiography

Peltier M, Vancraeynest D, Pasquet A, Ay T, Roelants V, D'hondt AM, Melin JA, Vanoverschelde JL.
Thirty-five patients referred for coronary angiography underwent RT-MCE and technetium-99m SPECT at baseline and after 0.84 mg/kg dipyridamole. Qualitative & quantitative analysis were performed and real-time MCE was shown to be both highly sensitive and specific for detection of CAD. The authors concluded that RT-MCE, with dipyridamole, can define the presence and severity of coronary disease in a manner that compares favourably with quantitative SPECT.
Reference: J Am Coll Cardiol. 2004; 43(2); 257-64

Non-invasive quantification of coronary blood flow reserve in humans using myocardial contrast echocardiography

Wei K, Ragosta M, Thorpe J, Coggins M, Moos S & Kaul S.
11 patients with normal epicardial coronary arteries (group I) and 19 with single-vessel coronary stenosis (group II) underwent angiography, MCE and CBF velocity measurements at rest and during intravenous adenosine infusion. In group I patients, MCE-derived myocardial blood flow (MBF) velocity reserve was similar to CBF velocity reserve using a Doppler flow wire. In group II patients, significant differences were found in MBF velocity reserve in patients with mild (<50%), moderate (50% to 75%), or severe (>75%) stenoses. A linear relation was found between flow velocity reserve determined using the 2 methods and the authors concluded that coronary flow reserve can be measured in humans using MCE.
Reference: Circulation 2001; 103(21); 2560-5

Detection of coronary artery disease with myocardial contrast echocardiography: comparison with 99mTc-sestamibi single-photon emission computed tomography

Kaul S, Senior R, Dittrich H, Raval U, Khattar R & Lahiri A.
This was the first study to compare MCE with nuclear imaging (SPECT) for detection of coronary artery disease. 30 patients with known or suspected CAD underwent MCE and 99mTc-sestamibi SPECT at baseline and after dipyridamole. Concordance between segmental scores was 92% (k=0.99) for both methods, between normal perfusion and reversible or irreversible segmental defects was 90% (k=0.80) and agreement between the two methods for each of the three vascular territories in each patient was 90% (k=0.77) and thus it was shown that MCE can provide similar diagnostic accuracy to SPECT for detection of CAD.
Reference: Circulation. 1997; 96(3); 785-92

MCE for detection of myocardial viability

Prognostic value of myocardial viability detected by myocardial contrast echocardiography early after acute myocardial infarction

Dwivedi G, Janardhanan R, Hayat SA, Swinburn JM, Senior R.
This study examined 95 patients who underwent low-power MCE following acute MI (87% thrombolysed for STEMI) and they were then followed up for 46±16 months. The extent of residual myocardial viability by MCE independently predicted hard end-points of cardiac death and repeat MI.
Reference: J Am Coll Cardiol (2007); 50; 327-34

Myocardial contrast echocardiography accurately reflects transmurality of myocardial necrosis and predicts contractile reserve after acute myocardial infarction

Janardhanan R, Moon JC, Pennell DJ, Senior R.
MCE and cardiac MRI (CMR) were performed in 42 patients 7-10 days after thrombolysis for STEMI. MCE was used to correlate perfusion with transmural extent of infarction (TEI) as defined by gadolinium-CMR. Contractile reserve was assessed with low-dose dobutamine 12 weeks following revascularization. Qualitative and quantitative MCE significantly inversely correlated with TEI and degree of contractile reserve. The study proved that MCE can refelct the transmurality of acute MI and, like CMR, predict the presence or absence of contractile reserve.
Reference: Am Heart J 2005;149(2):355-62

Identification of hibernating myocardium with quantitative intravenous myocardial contrast echocardiography: comparison with dobutamine echocardiography and thallium-201 scintigraphy

Shimoni S, Frangogiannis NG, Aggeli CJ, Shan K, Verani MS, Quinones MA, et al.
Patients with ischaemic cardiomyopathy underwent MCE (n=20), dobutamine echocardiography (n=18) and thallium scintigraphy (n=16) 1-5 days prior to planned CABG surgery. Repeat echocardiography was performed at 3-4months. Quantitative MCE parameters were significantly different between dysfunctional segments that recovered function (hibernating) versus those which remained dysfunctional. MCE had similar senstitity to thallium scanning and superior specificity for predicting functional recovery on a segmental level.
Reference: Circulation 2003;107(4):538-44

Microvascular structural correlates of myocardial contrast echocardiography in patients with coronary artery disease and left ventricular dysfunction: implications for the assessment of myocardial hibernation

Shimoni S, Frangogiannis NG, Aggeli CJ, Shan K, Quinones MA, Espada R, et al.
In this study, 20 patients underwent triggered MCE during continuous contrast infusion 24hrs prior to myocardial biopsy at time of CABG surgery. Quantitative parameters correlated closely with microvascular and capillary density and inversely correlated with collagen content (i.e. fibrosis). The study showed that microvascular integrity is directly related to MCE parameters and that these parameters can predict functional recovery following revascularisation.
Reference: Circulation 2002;106(8):950-6


MCE reviews & guidelines

Contrast echocardiography: evidence-based recommendations by European Association of Echocardiography

Senior R, Becher H, Monaghan MJ, Agati L, Zamorano J, Vanoverschelde JL & Nihoyannopoulos P.
A comprehensive 18-page EAE-endorsed document outlining the evidence base for the use of contrast agents in all aspects of clinical cardiology.
Reference: Eur J Echocardiogr 2009; 10 (2); 194- 212

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

 Mulvagh SL, Rakowski H, Vannan MA, Abdelmoneim SS, Becher H, Bierig SM, Burns PN, Castello R, Coon PD, Hagen ME, Jollis JG, Kimball TR, Kitzman DW, Kronzon I, Labovitz AJ, Lang RM, Mathew J, Moir WS, Nagueh SF, Pearlman AS, Perez JE, Porter TR, Rosenbloom J, Strachan GM, Thanigaraj S, Wei K, Woo A, Yu EH, Zoghbi WA.
A comprehensive 23-page document from the ASE providing a thorough overview of the principles of use of contrast agents and, similar to the EAE guideline, a summary of the evidence base supporting the use of contrast agents, including in the ITU and paediatric settings.
Reference: J Am Soc Echocardiogr. 2008; 21(11); 1179-201

The clinical applications of myocardial contrast echocardiography

Rakhit DJ, Becher H, Monaghan M, Nihoyannopoulos P, Senior R.
A BSE-endorsed supplement outlining the evidence base for utilising contrast agents for the assessment of myocardial perfusion (using MCE). Detection of coronary disease, assessing severity of coronary disease, post infarct imaging and viability assessment are all discussed.

Reference: Eur J Echocardiogr 2007;8(3):S24-9

Safety of contrast agents

Safety and Efficacy of Commercially Available Ultrasound Contrast Agents for Rest and Stress Echocardiography: A Multicenter Experience.

Dolan MS, Gala SS, Dodla S, Abdelmoneim SS, Xie F, Cloutier D, Bierig M, Mulvagh SL, Porter TR, Labovitz AJ. 
Reference: Journal of the American College of Cardiology 2009;53:32-38.

Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients)

Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M.
A retrospective review of over 4 million patients who received UCA (Definity) between 2002 – 2007. There was no increase in mortality with UCA and, in fact, pts receiving UCA for echo study were 24% LESS likely to die within 1 day of the study. This included severely unwell patients on intensive or high dependency care units.
Reference: Am J Cardiol 2008;102(12):1742-6

Safety of myocardial flash-contrast echocardiography in combination with dobutamine stress testing for the detection of ischaemia in 5250 studies

Aggeli C, Giannopoulos G, Roussakis G, Christoforatou E, Marinos G, Toli C, et al.
A Greek study of 5250 patients undergoing low MI & high MI MCE combined with dobutamine. There was no increase in death / acute MI using contrast and a low incidence of side-effects.
Reference: Heart 2008;94(12):1571-7

The safety of deFinity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses

Wei K, Mulvagh SL, Carson L, Davidoff R, Gabriel R, Grimm RA, et al.
Retrospective study from 13 sites performing echo studies between January 1, 2001-September 30, 2007. In total, 66,164 doses of Definity and 12,219 doses of Optison (5% of transthoracic/28% stress) were administered. Severe adverse events (SAEs) occurred in 8 patients (0.01%), anaphylactoid reactions in 4 patients (0.006%), there were no deaths and no SAE in hospitalized patients. In conclusion, ultrasound contrast was shown to be a very safe agent and as safe as – if not more safe – than other contrast agents used in other imaging modalities.
Reference: J Am Soc Echocardiogr 2008;21(11):1202-6

Product safety compromises patient safety (an unjustified black box warning on ultrasound contrast agents by the Food and Drug Administration).

This viewpoint paper shows the catastrophic sequences of inaccurate assessment of LV function and misdiagnosis of complications such as pseudoaneurysms and thrombi. In summary, warning and educating health care providers about previously unrecognized risks is important but clinical evidence shows that contrast echocardiography is safe in practice.
Even if there would be a moderate risk by the contrast agent, the risk/benefit still would be very favourable for using contrast agents even in acute myocardial infarction.
References:Grayburn PA. Am J Cardiol. 2008 Mar 15;101(6):892-3

FDA. United States Food and Drug Administration Center for Drug Evaluation and Research alert for healthcare providers

Comments :
In April 2008, the US Food and Drug Administration (FDA) performed a safety review of the US-approved perflutren microsphere contrast agents (Definity and Optison) and revised a previous black box warning. The new contraindications are much less restrictive than the previous contraindications and satisfy the needs of clinical echocardiography.

The Safety of Definity and Optison for Ultrasound Image Enhancement: A Retrospective Analysis of 78,383 Administered Contrast Doses.

Wei K, Mulvagh SL, Carson L, Davidoff R, Gabriel R, Grimm RA, Wilson S, Fane L, Herzog CA, Zoghbi WA, Taylor R, Farrar M, Chaudhry FA, Porter TR, Irani W, Lang RM, FESC. 
Reference: Journal of the American Society of Echocardiography 2008;21:1202-1206.

Safety of Contrast Administration for Endocardial Enhancement During Stress Echocardiography Compared With Noncontrast Stress.

Shaikh K, Chang SM, Peterson L, Rosendahl-Garcia K, Quinones MA, Nagueh SF, Kurrelmeyer K, Zoghbi WA.
Reference: The American Journal of Cardiology 2008;102:1444-1450.

Acute Mortality in Hospitalized patients Undergoing Echocardiography With and Without an Ultrasound Contrast Agent: Results in 18,671 Consecutive Studies.

Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML.
Reference: Journal of the American College of Cardiology 2008;51:1704-1706.

Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients).

Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M.
Serial retrospective studies showing the safety of contrast ultrasound agents in various clinical conditions, at rest or during stress, including critically ill patients and using various settings.
Reference: Am J Cardiol 2008;102:1742-6

Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies

Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML.
18,671 patients who underwent echocardiography within 24hrs of hospital admission (Jan 2005 – Oct 2007) were included in this retrospective analysis (12,475 unenhanced scans, 6,196 Definity contrast used). Vital status at 24 hours available for all patients and there was no difference in mortality between the two groups.
Reference: J Am Coll Cardiol 2008; 51(17):1704-6

Safety of contrast-enhanced echocardiography within 24 h after acute myocardial infarction.

Nucifora G, Marsan NA, Siebelink HM, van Werkhoven JM, Schuijf JD, Schalij MJ, Poldermans Dm FESC, Holman ER, Bax JJm FESC
Although performed in low risk patients, the present study provides further reassurance about the safety of LUMINITY in the acute phase of myocardial infarction. Administration of echo contrast did not induce any significant change in vital signs, physical examination, and ECG. There were no serious adverse events.
Reference: Eur J Echocardiogr 2008;9:816-8

Microbubbles in ultrasound-triggered drug and gene delivery.

Hernot S, Klibanov AL. 
When bio-effects of ultrasound contrast agents in combination with ultrasound exposure are used for ultrasound-triggered drug and gene delivery. An extensive review of the potential role of contrast echo for therapy. 
Reference: Advanced Drug Delivery Reviews 2008;60:1153-1166

Release of cardiac bio-markers during high mechanical index contrast-enhanced echocardiography in humans

Vancraeynest D, Kefer J, Hanet C, FESC, Fillee C, Beauloye C, Pasquet A, Gerber BL, FESC, Philippe M, Vanoverschelde JL, FESC.
This study showed that Myocardial Contrast Echocardiography can cause sub-clinical release of bio-markers in humans.
Reference: Eur Heart J. 2007 May;28(10):1236-41

Bio-effects of ultrasound contrast agents in daily clinical practice: fact or fiction?

Van Camp G, FESC, Droogmans S, Cosyns B.
In extreme situations, rarely seen in clinical practice, the concomitant use of ultrasound and contrast agents can lead to bio-effects in vitro, ex vivo, in animal studies, and in humans. Techniques using low volumes of contrast agents with low-MI imaging should be preferentially used. Each echolaboratory using contrast should have experience with the use of ultrasound enhanced contrast and should be able to treat serious allergic reactions.
Reference: Eur Heart J. 2007 May;28(10):1236-41.

Food and drug administration prescribing information for Definity approved October 2007

Black box warning from the FDA for perfluten-containing ultrasound contrast agents, quoting post-marketing reports of four deaths occurring within 30 minutes of administration of Definity.

Thinking outside the "box" the ultrasound contrast controversy

Main ML, Goldman JH, FESC, Grayburn PA.
Regarding the Black box warning from the FDA for perfluten-containing ultrasound contrast agents. These warnings ignore the proven efficacy of ultrasound contrast agents, the previously established safety of these compounds, the potential risks of alternative procedures, and the likely confounding effect of pseudocomplication. The authors suggest that the FDA Medical Imaging Division convene a panel of cardiologists experienced in a variety of imaging modalities to fully assess the adverse events that have been attributed to these agents.
Reference: J Am Coll Cardiol. 2007 Dec 18;50(25):2434-7

Microvascular permeabilization and cardiomyocyte injury provoked by myocardial contrast echocardiography in a canine model

Miller DL, Driscoll EM, Dou C, Armstrong WF, Lucchesi BR.
This study advances our knowledge of the toxicity area by carefully examining the effects of destruction of a commercially available contrast agent (Definity, Bristol Myers-Squibb, Billerica, Massachusetts) using a clinical ultrasound machine (Vingmed System V, General Electric, Cincinnati, Ohio) and standard ultrasonic acoustic power settings in a dog model. There was an increased vascular permeability present mainly in a transmural pattern across the anterior wall. There was an increased propidium iodide staining was present in all six open-chest dogs that received bubbles and cardiac ultrasound. Finally, the authors showed no evidence of ventricular ectopy in sham treatment or the lower power setting (?1.2 MPA) but a substantial increase in premature ventricular contractions with higher acoustic power (?2.2 MPA) in the open chest model.
Reference: J Am Coll Cardiol. 2006 Apr 4;47(7):1464-8

Safety of dobutamine stress real-time myocardial contrast echocardiography

Tsutsui JM, Elhendy A, FESC, Xie F, O’Leary EL, McGrain AC, Porter TR.
The hemodynamic and adverse effects of real-time contrast echocardiography (RTCE) using Definity® and Optison® in 1.486 patients who underwent dobutamine stress echocardiography over a four-year period were compared with 1,012 patients who underwent conventional dobutamine stress echocardiography (DSE) without contrast. Dobutamine stress RTCE appeared to be a safe and feasible technique for evaluating patients with known or suspected CAD. There was no difference in the incidence of nonsustained ventricular tachycardia, sustained ventricular tachycardia, or supraventricular tachycardia during dobutamine infusion between RTCE and DSE. Myocardial perfusion imaging with RTCE had a higher accuracy for detecting patients with angiographically significant CAD than the analysis of wall motion (84% vs. 66%, respectively; p < 0.001).
Reference : J Am Coll Cardiol 2005; 45.1235-42.

Methodological Issues/Technique

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

Mulvagh SL, Rakowski H, Vannan MA, Abdelmoneim SS, Becher H, Bierig SM, Burns PN, Castello R, Coon PD, Hagen ME, Jollis JG, Kimball TR, Kitzman DW, Kronzon I, FESC, Labovitz AJ, Lang RM, FESC, Mathew J, Moir WS, Nagueh SF, Pearlman AS, Perez JE, Porter TR, Rosenbloom J, Strachan GM, Thanigaraj S, Wei K, Woo A, Yu EHC, Zoghbi WA.
A review of the applications for contrast echocardiography and their impact on cardiac diagnosis.
Reference: Journal of the American Society of Echocardiography 2008;21:1179-1201

Myocardial contrast echocardiography: a 25-year retrospective.

Kaul S, FESC.
A 25-year retrospective review on MCE with emphasis on more recent developments and remaining challenges for the field.
Reference: Circulation. 2008 Jul 15;118(3):291-308

Recommendations for chamber quantification

Lang RM, FESC, Bierig M, Devereux RB et al.
Indications to when to use contrast enhancement in this critical review of the literature and an update of recommendations on how to quantitate cardiac chambers using echocardiography made jointly by the American Society of Echocardiography and European Association of Echocardiography.
Reference: Eur J Echocardiogr. 2006;7:79-108

Left Ventricular Volumes and Regional Wall Motion

Analysis of regional wall motion during contrast-enhanced dobutamine stress echocardiography: effect of contrast imaging settings.

Cosyns B, Van Camp G, Droogmans S, Weytjens C, Schoors D, Lancellotti P.
Despite the similar improvement in endocardial border delineation, LVO settings allow the detection of more WMA than MCE at peak stress, leading to a significantly higher accuracy for the detection of ischaemia in patients suspected of coronary artery disease when only wall motion is taken into account.
Reference: Eur J Echocardiogr. 2009 Dec;10(8):956-60

Real-time 3-dimensional echocardiography early after acute myocardial infarction: Incremental value of echo-contrast for assessment of left ventricular function.

Gaetano Nucifora, Nina Ajmone Marsan, Eduard R. Holman, Hans-Marc J. Siebelink, Jacob M. van Werkhoven, Arthur J. Scholte, Ernst E. van der Wall, Martin J. Schalij, Jeroen J. Bax
Assessment of LV systolic function in AMI patients with RT3DE is frequently hampered by suboptimal echocardiographic quality. Contrast-enhanced RT3DE is of incremental value, improving the endocardial border visualization and the reproducibility of LV function assessment.
Reference: American Heart Journal, Volume 157, Issue 5, May 2009, Pages 882.e1-882.e8

Impact of contrast echocardiography on evaluation of ventricular function and clinical management in a large prospective cohort.

Kurt M, Shaikh KA, Peterson L, Kurrelmeyer KM, Shah G, Nagueh SF, Fromm R, Quinones MA, Zoghbi WA
The utilization of CE in technically difficult cases improves endocardial visualization and impacts cardiac diagnosis, resource utilization, and patient management.
Reference: J Am Coll Cardiol. 2009 Mar 3;53(9):802-10

Left ventricular volume measurement with echocardiography: a comparison of left ventricular opacification, three-dimensional echocardiography, or both with magnetic resonance imaging.

Jenkins C, Moir S, Chan J, Rakhit D, Haluska B, Marwick TH, FESC.
A comparison of enhanced and non-enhanced contrast 2DE and 3DE with MRI as gold standard. The main findings of this study of patients with previous infarction are that the improvement in accuracy of estimation of LV volume and EF with CE-2DE is analogous to that of NC-3DE, and that techniques led to similar improvement in categorization of patients according to EF. However, CE-3DE is feasible and technically superior to NC-2DE, NC-3DE, and CE-2DE.
Reference: Eur Heart J 2009;30:98-106

A Randomized Cross-Over Study for Evaluation of the Effect of Image Optimization With Contrast on the Diagnostic Accuracy of Dobutamine Echocardiography in Coronary Artery Disease The OPTIMIZE Trial.

Plana JC, Mikati IA, Dokainish H, Lakkis N, Abukhalil J, Davis R, Hetzell, Zoghbi W.
There was no impact of contrast agent use on the agreement of dobutamine stress
echocardiography (DSE) with angiography (accuracy) if the confidence of interpretation
was high in unenhanced studies. However, a significant impact was seen when the con-
fidence of interpretation was low, with an intermediate effect in studies with medium
Reference: J Am Coll Cardiol Img 2008;1:145–52

Analysis of myocardial perfusion or myocardial function for detection of regional myocardial abnormalities. An echocardiographic multicenter comparison study using myocardial contrast echocardiography and 2D echocardiography.

Hoffmann R, FESC, Borges AC, Kasprzak JD, FESC, von Bardeleben S, Firschke C, FESC, Greis C,
Engelhardt M, Becher H, Vanoverschelde JL.
Qualitative estimation of myocardial perfusion contrast echo is inferior to contrast enhanced 2D echocardiography with regard to visibility of all LV segments and appears slightly inferior with regards to interobserver agreement (IOA), while both are superior to unenhanced 2D echocardiography. The methods demonstrated high accuracy in detection of panel defined regional myocardial abnormalities.
Reference: Eur J Echocardiogr 2007;8:438–448

Analysis of regional left ventricular function by cineventriculography, cardiac magnetic resonance imaging, and unenhanced and contrast-enhanced echocardiography: a multicenter comparison of methods

Hoffmann R, FESC, von Bardeleben S, Kasprzak JD, FESC, Borges AC, ten Cate F, FESC, Firschke C, FESC, Lafitte S, Al-Saadi N, Kuntz-Hehner S, Horstick G, Greis C, Engelhardt M, Vanoverschelde JL, FESC, Becher H.
Comparison of conventional and contrast-enhanced echocardiography, biplane cine angiography, and cardiac magnetic resonance for the detection of regional wall motion abnormalities. The study underlines the utility of contrast-enhanced echocardiography in comparison to the other methods. Although some limitations due to patients selection and the absence of data regarding the baseline quality of echocardiographic images, an unexpected lesson from this study arose with the interpretation of cardiac magnetic resonance imaging, showing an interobserver agreement much worse than expected.
Reference: J Am Coll Cardiol. 2006 Jan 3;47(1):121-8

Contrast administration reduces interobserver variability in determination of left ventricular ejection fraction in patients with left ventricular dysfunction and good baseline endocardial border delineation

Nayyar S, Magalski A, Khumri TM, Idupulapati M, Stoner CN, Kusnetzky LL, Coggins TR, Morris BA, Main ML, FESC.
This study has shown improved interobserver variability even in patients with good baseline endocardial border definition.
Reference: Am J Cardiol. 2006 Oct 15;98(8):1110-4

Myocardial Perfusion

Myocardial Contrast Echocardiography Enhances Long-Term Prognostic Value of Supine Bicycle Stress Two-Dimensional Echocardiography.

Tomasz Miszalski-Jamka, Stefanie Kuntz-Hehner, Harald Schmidt, Daniel Peter, Karol Miszalski-Jamka, Christoph Hammerstingl, Klaus Tiemann, Alexander Ghanem, Clemens Troatz, Mieczysław Pasowicz, Berndt Lüderitz, Heyder Omran.
MCE enhances the predictive power of supine bicycle stress 2DE and allows the risk stratification of patients with normal results on 2DE.
Reference: Journal of the American Society of Echocardiography, Volume 22, Issue 11, November 2009, Pages 1220-1227

Impact of previous myocardial infarction on the incremental value of myocardial contrast to two-dimensional supine bicycle stress echocardiography in evaluation of coronary artery disease.

Tomasz Miszalski-Jamka, Stefanie Kuntz-Hehner, Harald Schmidt, Karol Miszalski-Jamka, Christoph Hammerstingl, Klaus Tiemann, Alexander Ghanem, Clemens Troatz, Mieczysław Pasowicz, Berndt Lüderitz, Heyder Omran.
MCE enhances sensitivity and accuracy of 2DE in detection of obstructive CAD during supine bicycle stress. The incremental benefit of MCE is especially present in patients without previous MI.
Reference: International Journal of Cardiology, Volume 136, Issue 1, 24 July 2009, Pages 47-55

The Extent of Microvascular Damage During Myocardial Contrast Echocardiography Is Superior to Other Known Indexes of Post-Infarct Reperfusion in Predicting Left Ventricular Remodeling.

Galiuto L, Garramone B, Scarà A, Rebuzzi AG, Crea F, FESC, La Torre , Funaro S, Madonna M, Fedele F, Agati L; AMICI Investigators.
This is the first multicentric study on MCE in acute myocardial infarction, demonstrating, in 110 patients that microvascular integrity at MCE is the most important predictor of LV remodeling, as compared with persistent ST segment elevation and myocardial blush grade.
Reference : J Am Coll Cardiol. 2008 Feb 5;51(5):552-9

Effects of Left Bundle-Branch Block on Cardiac Structure, Function, Perfusion, and Perfusion Reserve: Implications for Myocardial Contrast Echocardiography Versus Radionuclide Perfusion Imaging for the Detection of Coronary Artery Disease.

Hayat SA, Dwivedi G, Jacobsen A, Lim TK, Kinsey C, Senior R, FESC.
In this paper, the authors demonstrate that left bundle branch block (LBBB) is associated with preserved flow but reduced coronary flow reserve. Interestingly, MCE appears superior to SPECT in the assessment of such flow changes, since SPECT is humpered by partial volume effect.
Reference : Circulation. 2008 Apr 8;117(14):1832-41. Epub 2008 Mar 31

Prognostic Value of Myocardial Viability Detected by Myocardial Contrast Echocardiography Early After Acute Myocardial Infarction

Dwivedi G, Janardhanan R, Hayat SA, Swinburn JM, Senior R, FESC.
In this interesting paper, the authors find that the extent of microvascular integrity at myocardial contrast echocardiography (MCE) is a powerful independent predictor of hard coronary events in patients after acute myocardial infarction. In fact, they demonstrate that contrast defect index <1.86 predicts survival in 99% of patients and contrast defect index <1.67 predicts survival or absence of recurrence of infarction in 95% of patients. Thus, ones more, MCE has demonstrated to have an important prognostic role after acute myocardiainfarction.
Reference : J Am Coll Cardiol. 2007 Jul 24;50(4):327-34. Epub 2007 Jul 6. 504 pp. 327-334

Myocardial contrast echocardiography for the detection of coronary artery stenosis: a prospective multicenter study in comparison with single-photon emission computed tomography

Jeetley P, Hickman M, Kamp O, Lang RM, FESC, Thomas JD, FESC, Vannan MA, Vanoverschelde JL, FESC, van der Wouw PA, Senior R, FESC.
In a prospective multicenter study MCE was compared with SPECT (a semiquantitative comparison) for the detection of coronary artery disease. In this population, with a high pretest probability of disease, there was no difference in the sensitivities of MCE and SPECT in the detection of CAD (84% vs. 82%) and both had similar specificities (56% vs. 52%), respectively. The authors contrast their results to a previous multicenter study that reported lower sensitivities and attribute their improved results to improved technology and expertise. There was no mention of patients excluded for image quality or segments/ regions that could not be visualized.
Reference: J Am Coll Cardiol. 2006 Jan 3;47(1):141-5

Quantitative adenosine real-time myocardial contrast echocardiography for detection of angiographically significant coronary artery disease

Malm S, Frigstad S, Torp H, Wiseth R, FESC, Skjarpe T.
55 consecutive patients, only 35 patients with a complete dataset. Although myocardial blood flow and myocardial blood flow velocity reserves can accurately identify significant coronary disease in selected patients, this technique is limited by imaging artifacts and timeconsuming analysis, and the diagnostic accuracy seems sufficient only for LAD stenosis.
Reference: J Am Soc Echocardiogr. 2006 Apr;19(4):365-72

Effect of coronary stenosis on adjacent bed flow reserve: assessment of microvascular mechanisms using myocardial contrast echocardiography.

Pacella JJ, Villanueva FS.
In an experimental study, epicardial flow (flow probe), total flow (epicardial and collateral contributions), flow through the microcirculation (vessels <10 µm [i.e., microspheres]), and regional myocardial blood volume (MCE) were measured separately to isolate the individual contributions to each flow territory. At baseline, LAD stenosis increased LCx epicardial flow without changing myocardial flow. During adenosine infusion, LCx flow reserve was significantly less during noncritical LAD stenosis than without stenosis. This result was associated with an increase in MCE-derived blood volume at end-systole. There was also a strong trend toward a negative linear relationship between stenosis severity and the magnitude of flow reserve reduction.
Reference: Circulation. 2006 Oct 31;114(18):1940-7

Collateral-flow measurements in humans by myocardial contrast echocardiography: validation of coronary pressure-derived collateral-flow assessment

Vogel R, Zbinden R, Indermühle A, Windecker S, FESC, Meier B, FESC, Seiler C, FESC.
Reference: Eur Heart J. 2006 Jan;27(2):157-65