European Journal of Echocardiography (2009) 10, 194–212doi:10.1093/ejechocard/jep005 EAE RECOMMENDATIONS Contrast echocardiography: evidence-basedrecommendations by European Associationof Echocardiography Roxy Senior1*, Harald Becher2, Mark Monaghan3, Luciano Agati4, Jose Zamorano5,Jean Louis Vanoverschelde6, and Petros Nihoyannopoulos7 1Department of Cardiology, Northwick Park Hospital, Imperial College, London, Harrow HA1 3UJ, UK; 2John RadcliffeHospital, Oxford, UK; 3King's College Hospital, London, UK; 4La Sapienza University, Rome, Italy; 5Hospital Clı´nico San Carlos,Madrid, Spain; 6Cliniques Universitaires St-Luc, Universite ´ Catholique de Louvain, Brussels, Belgium; and 7Hammersmith Hospital, Imperial College, London, UK Received 30 December 2008; accepted 11 January 2009 This paper examines the evidence for contrast echocardiography, both for improving assessment of left ventricular structure and function compared with unenhanced echocardiography and for the identifi- cation of myocardial perfusion. Based on the evidence, recommendations are proposed for the clinicaluse of contrast echocardiography.
(which has relatively lower myocardial blood volume).
With the advancement in ultrasound techniques and In a significant proportion of patients, echocardiography improved microbubble technology, it is now possible also fails to produce diagnostically useful images despite tissue to assess myocardial microcirculation and hence perfusion.
harmonic imaging.1 The main impediments appear to be This paper examines the clinical efficacy and safety of obesity and lung disease.2 The problem is even greater in ultrasound contrast agents and proposes evidence-based patients referred for stress echocardiography as images recommendations and protocols for the use of contrast are suboptimal in as many as 33% of the patients.3 This echocardiography in various clinical scenarios.
results in inaccurate assessment of left ventricular (LV) func-tion, and suboptimal reproducibility especially in the sub-group subsequent referrals for other tests because of uninterpre- Echogenicity and ultrasound properties are determined by table images.
the size, shell, and encapsulated gas characterizing the These concerns prompted the facilitation of contrast microbubbles within the various contrast agents. Micro- ultrasound imaging that utilizes contrast agents. The bubble ultrasound scatter is proportional to the sixth present generation of ultrasound contrast agents consist of power of the radius, so the largest bubble capable of microbubbles of encapsulated high-molecular-weight gas.
passing through the pulmonary microcirculation will have Since the ultrasound characteristics of microbubbles are dis- the best acoustic profile.4 The harmonic properties of micro- tinctly different from those of the surrounding blood cells bubbles are a function of their non-linear oscillation, which and cardiac tissue, the backscatter that they produce means that they reflect sound not only at the fundamental result in intense echocardiographic signals, which are pro- frequency of the ultrasound source but also at higher harmo- portional to the blood volume. Thus, the LV cavity is nics.5 A microbubble's ultrasonic characteristics also depend enhanced compared with the surrounding heart muscle on its size, the composition of the outer shell of the bubble,and the encapsulated gas.5 In general, the more elastic theshell, the more easily it will be compressed in an ultrasonic * Corresponding author. Tel: þ44 20 8869 2547/2548; fax: þ44 20 8864 field and the better it will resonate. Conversely, stiffer E-mail address: roxysenior@cardiac-research.org Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009.
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Evidence-based recommendations by EAE on contrast echocardiography Characteristic of currently available contrast agents in UK and Europe Sulphur hexafluoride Naturally occurring lipids Contraindications and precautionsPatients experiencing side effects 11 in clinical trials (%) Most frequent side effects in Headache (2.1%), nausea (1.3%), Headache (5.4%), nausea and/ Headache (2.0%), flushing (1.0%), chest pain (1.3%), taste or vomiting (4.3%), warm back pain (0.9%). rash/ perversion (0.9%), sensation or flushing (3.6%), hyperglycaemia (0.6%), injection dizziness (2.5%).
site reaction 0.6%), paresthesia(0.6%), vasodilation (0.6%),injection site pain (0.5%).
Bracco Diagnostics Lantheus Medical Imaging (formerly Bristol-Myers Squibb) The microbubbles must be stable enough to resist destruc- Pulse 1 are subtracted from that derived from Pulse 2, and tion at normal ultrasound power outputs and so maintain a the difference represents the contrast signal since the sufficient concentration in the heart to give a satisfactory tissue signal cancels out. Newer high power techniques image. This is largely a factor of solubility of the gas in also utilize ultraharmonic properties of the microbubble, which improves the detection of the ‘signal' of the micro- soluble and so more stable.5 Characteristics of the three- bubble, from the ‘noise' of the background tissue, since marketed second-generation contrast agents that use tissue produces very little ultraharmonic signal.10 high-molecular-weight gases are listed in Table 1.6–8 In order to use real-time imaging of contrast within the LV cavity and/or myocardium, it is necessary to reduce signifi- Contrast imaging modalities cantly the transmitted ultrasound power (low MI imaging)and this has required more sophisticated, contrast-specific As previously mentioned, harmonic imaging utilizes the non- imaging modalities.11 These modalities have unique fea- linear scattering properties of ultrasound contrast agents to tures, and have been named according to the developing facilitate their detection within the heart. However, tissue ultrasound system manufacturer: power pulse inversion, also generates a harmonic signal as ultrasound is propagated power modulation, and cadence (or coherent) contrast through it and a high-quality contrast-enhanced image is one imaging. They essentially work by transmitting multiple where the distribution of contrast (within the LV cavity and/ pulses down each scan line. Alternate pulses are 1808 out or myocardium) is clearly seen without the presence of con- of phase with other or vary in magnitude of amplitude by founding myocardial tissue signals. The mechanical index a fixed ratio, or are a combination of both strategies. All (MI) is a measure of the power generated by an ultrasound these types of modalities rely on the fact that tissue is transducer within an acoustic field. Harmonic imaging essentially a linear and relatively predictable ultrasound requires relatively high ultrasound power (high MI) that scatterer, especially at low ultrasound energy levels, very quickly destroys (bursts) most commercially available whereas contrast microbubbles are not, and are therefore ultrasound contrast agents and therefore is not a suitable described as being ‘non-linear'. When alternate backscat- imaging modality for continuous, or ‘real-time' contrast tered signals are received, which are perfectly out of imaging. High MI contrast imaging modalities have been suc- phase or proportionally altered in amplitude, they are pro- cessfully utilized for the detection of myocardial contrast cessed by the imaging software as being derived from using intermittent or triggered imaging modes where one tissue and therefore are filtered out and suppressed. All imaging frame is created every one, two, three, or up to remaining ‘non-linear' signals are considered to be derived six cardiac cycles. The most common form of high MI from contrast microbubbles and are displayed. When using imaging modality used in this way is harmonic power this kind of imaging modality, the image will normally be Doppler, which works best when utilized with a fragile con- totally dark prior to contrast administration, confirming trast agent which is quickly destroyed and contains a soluble effective suppression of tissue data. This type of imaging gas (air or nitrogen).9 This typically involves a dual-pulse is very effective for LV endocardial border enhancement, technique where the difference in backscattered signal as it demonstrates a sharp demarcation between the from two high MI pulses transmitted down each scan line is contrast-enhanced cavity and the myocardium. With minor examined. If contrast micro-bubbles are encountered by modification and increased contrast concentration, it can the first pulse, they will generate a backscattered signal also effectively detect and display contrast within the myo- and also be destroyed. In addition, any tissue targets will cardium, facilitating the evaluation of myocardial perfusion also generate a signal. The second pulse will only generate as described later.11 It is common to combine this form of a signal from tissue because all contrast will have been low MI contrast imaging with a burst of a few frames of destroyed by the first pulse. The backscattered data from high MI imaging to destroy contrast within the myocardium.
R. Senior et al.
This allows the qualitative and quantitative assessment of segments on non-contrast echocardiography. Outcomes contrast replenishment into the myocardium and is also dis- were assessed both by the institutional investigator and by cussed later.
blinded, independent physicians or sonographers who hadno clinical information available to them. A primary end- Efficacy of contrast agents in echocardiography point in all studies was change in EBD from baseline, and sig-nificant improvements in this parameter were seen by a Enhancement of left ventricular endocardial border total of 12 of 16 of the blinded readers.12 In three studies,involving 190 patients in total, LV enhancement was also a In all of the following studies described, all patients had sub- primary endpoint. In two of the studies, blinded readers optimal images with non-contrast echocardiography before reported enhancement in up to 78% of participants. In the the use of a contrast agent. There have been three con- remaining study, the ability of investigators to optimize trolled studies of SonoVue in echocardiography.6 A total of echocardiographic equipment settings led to even better 317 patients were treated with doses of SonoVue (between results with blinded readers reporting 86–98% enhance- 0.5 and 4.0 mL) or with a comparator drug that was an ment.12 An overview of the studies providing proof of con- older microbubble contrast agent or saline. Primary end- trast enhancement of endocardial border definition in points were assessed by two blinded readers. In all three echocardiography is provided in Table 2.
studies, SonoVue administration resulted in increases inendocardial border delineation (EBD) score and left ventri- Quantitative assessment of left ventricular function cular opacification (LVO) score relative to baseline images,which were significantly greater than after administration Left ventricular function assessment provides valuable of the comparator or saline (P , 0.001). In the two studies diagnostic and prognostic information in patients with sus- in which it was a primary endpoint, duration of useful con- pected cardiovascular disease. Accurate and reproducible trast was 1.7–4 min with SonoVue (2.0 mL) compared with measurement of LV function is imperative for reliability of ,15 s with the highest dose of comparator. For all primary information. Several studies, as shown in Table 3, have indi- endpoints (LVO and EBD scores, and duration of effect), cated that contrast-enhanced echocardiography improves the maximum effect observed with SonoVue was signifi- the evaluation of LV volumes and ejection fraction cantly greater than that achieved with the comparator.
(LVEF).13–22 These findings were most striking in study par- Optison and Albunex were used in two similar multicen- ticipants who had two or more adjacent poorly visualized tre, randomized crossover studies.7 The test drugs were administered single blind and the image analysis was per- However, in a larger study consisting of 110 patients, the formed double blind. A total of 203 patients participated accuracy of intravenous contrast echocardiography was with the criteria for inclusion being that at least two of six found to be significantly better than unenhanced tissue har- segments of the LV endocardial border were not well deli- monic imaging when compared with cardiac magnetic reson- neated at routine echocardiography. Images were inter- ance (CMR) imaging irrespective of imaging quality.18 It is preted by a reader who was blinded to the patient's now known based on contrast studies that LV volumes clinical history and to the identity and dose of the test assessed by tissue harmonic imaging were consistently drug. In comparison with non-contrast ultrasound, Optison smaller, while those assessed during contrast echocardiogra- significantly increased the length of endocardial border phy were more comparable with cardiac MRI. This is prob- that could be visualized both at end-systole and end- ably because tissue harmonic imaging does not track the diastole. In addition, Optison significantly improved the true endocardial surface as well as contrast echocardiogra- ability to delineate qualitatively each of the LV segments, phy, resulting in tracking noise in the LV cavity that is per- with a lesser effect for the septal segments. As assessed ceived as the endocardial border. In a multicentre study19 by video densitometry, Optison increased LV opacification using SonoVue, LV volumes and LVEF assessed by contrast in the mid-chamber and apical views.
echocardiography demonstrated the least reader variability Four controlled studies were performed with Luminity in a compared with unenhanced echocardiography, cine ventri- total of 249 patients with two or more non-evaluable culography, and cardiac MRI. When regional function was Efficacy of contrast agents on various measures of image enhancement in echocardiography (Modified from Bhatia and Senior)102 Contrast agent used vs.
Measure of contrast enhancement comparator or control Optison vs. Albunex Sonovue vs. Albunex vs. saline Upward arrows signify significant improvement and horizontal arrows signify no significant difference in side effects compared with control.
LVB, left ventricular border; LVO, left ventricular opacification; LVEB, left ventricular endocardial border delineation score.
Efficacy of contrast echocardiography for the assessment of left ventricular ejection fraction volumes or regional wall motion abnormalities (Adapted from Bhatia and Senior)102 Agreement vs. comparator* Hoffmann et al.19 Mean correlation coefficient [95% CI] 0.85 (EF)[0.82–0.88] 0.94 (EF)[0.91–0.97] 0.81 (EDV)[0.6–1.02] 0.94 (EDV)[0.92–0.96] 0.92 (ESV)[0.87–0.97] Mean % agreement with gold standard Figures in bold refer to correlation coefficient. Percentage values refer to mean extent of agreement with standard unless otherwise stipulated.
RNI, radionuclide imaging; TEE, transoesophageal echocardiography; LV, left ventricle; EDV, end-diastolic volume; ESV, end-systolic volume; EF, ejection fraction; RWMA, regional wall motion abnormalities; FI, funda- mental imaging; HI, harmonic imaging; CMR, cardiac magnetic resonance imaging.
aNo gold standard: direct comparison between standard, harmonic, and contrast echo. Values refer to percentage of patients in whom EF could be calculated with certainty.
bExpert panel decision as gold standard, but patients also underwent CMR. Values refer to Kappa extent of agreement with expert panel consensus.
cValues refer to percentage of diagnostic stress echocardiograms in difficult-to-image patients within a trial.
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evaluated, the assessment by contrast echocardiography had required further diagnostic testing compared with only demonstrated the highest accuracy compared with cardiac 17% of those with enhanced images.
MRI or cineventriculography. Such results have major impli- It has been estimated that the addition of contrast media cations for screening patients before and following them up gives 37% more diagnostic information and, in patients after chemotherapy, because one needs the most reproduci- with a poor acoustic window, 50–90% improvement has ble technique to track changes in LV function so that timely been observed.22 In addition, it has been pointed out that action may be taken. In this scenario, contrast echocardio- contrast agents enhance decision-making for echocardiogra- graphy is likely to be the non-invasive technique of choice phers and clinicians as well as shortening the time to diagno- due to its low risk (non-ionizing) and portability.
sis.22 Contrast enhancement may also improve clinical The ability of contrast echocardiography to assess LV throughput by decreasing the time needed to image remodelling, a major indicator of prognosis, 7–10 days after acute myocardial infarction (AMI) was evaluated.20Compared with cardiac MRI, the study demonstrated that Clinical efficacy of stress contrast contrast echocardiography was more accurate and reprodu- cible than tissue harmonic imaging alone. Furthermore, con-trast echocardiography correctly identified patients with various grades of LVEF. Such findings are clinically important through improved endocardial border definition during because LVEF after AMI is one of the major determinants not stress echocardiography has been shown in many studies only of outcome but also for decision-making regarding, for (Table 4). Image quality is a key factor determining the diag- example, the implantation of an expensive, but life saving, nostic accuracy of stress echocardiography. Contrast has device like intracardiac cardioverter defibrillator (ICD).
been shown to improve visualization of regional wall The accuracy of contrast echocardiography for assessing motion abnormalities, improve study quality, and increase LV volumes and LVEF was also demonstrated in critically ill reader confidence in study interpretation.23–25 patients in intensive therapy units where accurate assess- Moir et al.26 demonstrated improved sensitivity and accu- ment of LV function is mandatory for optimal management racy for the detection of CAD when contrast was adminis- but often has to be performed under adverse imaging cir- cumstances.17 In addition, it has been shown that contrast echocardiography improves the interpretation of regional patients with good LV visualization at rest with that in and global LV function in intensive care unit patients.14 In patients with poor image quality during native imaging a further evaluation of similar group of patients, comparing that underwent contrast echocardiography.23,27 These inves- the results with transoesophageal echocardiography, it was tigators found that, in patients with poor image quality, the concluded that the use of intravenous contrast harmonic use of contrast during dobutamine stress echocardiography echocardiography significantly improved the feasibility and significantly improved EBD and resulted in a sensitivity and accuracy of estimated LVEF over tissue harmonic imaging.17 specificity for the detection of CAD comparable with that A randomized study evaluated the use of Luminity for the achieved with the native dobutamine stress in patients detection of coronary artery disease (CAD) in 560 patients in with good image quality. In a recent randomized control whom non-contrast stress echocardiography had given trial by Plana et al.28 comparing the diagnostic accuracy difficult-to-interpret images.21 Patients were randomized for the detection of CAD in patients who received contrast to receive rest and stress echocardiography either enhanced vs. those who did not, accuracy of contrast dobutamine with Luminity or unenhanced. Investigator confidence was stress echocardiography was significantly higher compared assessed as excellent or good in 95% of the enhanced with unenhanced stress echocardiography for the detection images compared with only 63% of unenhanced images (P , 0.0001). Of the enhanced images, 95% proved diagnos- In another study, stress echocardiography with contrast tic compared with 66% of unenhanced images. Three months (30% of patients) resulted in reduced down stream cost com- after the imaging, 36% of patients with unenhanced imaging pared with Ex-ECG for the detection of CAD in patients Contrast for endocardial border delineation in stress echocardiography Number of subjects Treadmill exercise Rainbird et al.25 Tsutsui et al.100 Korosoglou et al.102 Ikonomides et al.103 Definity, perflutren lipid microspore; Levovist, galactose/palmitic acid microcrystal suspension; Optison, perflutren protein-type A microspheres; Sonazoid, DB723/NC100100, perflubutane microsperes.
aAlso perfusion.91 Evidence-based recommendations by EAE on contrast echocardiography presenting with troponin negative acute chest pain andenabled more patients to be discharged rapidly from the Comparative mortality in selected cardiac procedures hospital.29 A study in the USA estimated that by reducing the need for further investigative procedures, contrastenhancement of sub-optimal images during stress echocar- 1:145 000 (SonoVue), 1:500 000 diography would result in a saving of $238 per patient.30 Studies have also shown that the inter-observer variability Myocardial Scintigraphy improved significantly following contrast administration for the interpretation of wall motion abnormalities and this is Coronary arteriography particularly true if the operators are in their learning Modified from Main et al.41 withdrawn by FDA following mounting evidence of safety Assessment of cardiac structure and unequivocably favourable risk–benefit profile in the Contrast echocardiography is now recognized as the tech- acute setting.36,38,42 It is hoped that EMEA will follow suit, nique of choice for establishing or excluding the presence of regarding Sonvue which has similar safety profile to Definity apical hypertrophic cardiomyopathy, LV thrombus, non- and Optison.37,38 At present, SonoVue may be used 7 days compaction of LV, and life-threatening complications of after ACS. However, in all acute conditions, it is important myocardial infarction, such as myocardial rupture and LV to monitor vital signs and pulse oximetry for 30 min after pseudoaneurysm.32–35 Contrast opacification facilitates the contrast administration. The only absolute contraindications identification of apical abnormalities. This is because native for administration of contrast agents are in patients with tissue harmonic echocardiography is unable to overcome the known or suspected intracardiac cardiac shunting of signifi- noise, clutter, and reverberation artefacts in the near field cant degree, or known hypersensitivity to the agent. Intra- as tissue harmonic signals are weak at the nearfield; hence, coronary administration is also not approved and is con- apical abnormalities can be difficult to visualize.
without complications in thousands of patients with hyper-trophic cardiomyopathy undergoing septal ablation.
Clinical safety of contrast agentsin echocardiography Indications, imaging modality, and contrast Contrast echocardiography is safe. In a large retrospective administration for left ventricular opacification analysis of .18 000 patients, of which one-third receivedcontrast agent in the acute setting, there was no significant Indications for resting left ventricular opacification difference in mortality in patients who received contrast vs.
those who did not.36 This is because patients who received In patients with suboptimal images: contrast agents had a higher risk clinical profile, comparedwith those who did not receive contrast. A European stress (1) To enable improved endocardial visualization and assess- ment of LV structure and function when two or more con- Optison, SonoVue, or no contrast, and found that the tiguous segments are NOT seen on non-contrast images overall incidence of adverse events was not different (2) To have accurate and repeatable measurements of LV between the three groups.37 Another UK study involving volumes, and ejection fraction by 2D Echo 4000 patients showed no difference in acute complication (3) To increase confidence of the interpreting physician in rate in patients who received contrast vs. those who did not the LV function, structure and volume assessments during stress echocardiography and this is despite the fact (4) To confirm or exclude the echocardiographic diagnosis that the patients in the contrast group were in the higher of the following LV structural abnormalities, when risk group.38 A study in the USA included 963 patients receiv- non-enhanced images are suboptimal for definitive ing Optison and 523 receiving Luminity during stress echo- cardiography and analysed adverse cardiovascular andpulmonary effects.39 The incidence of side effects did not † apical hypertrophic cardiomyopathy differ significantly between the three groups (Optison, Defi- † ventricular non-compaction nity, and no contrast). Finally, a recent report of dobuta- † apical thrombus mine myocardial stress echocardiography of over 5000 † ventricular pseudoaneurysm patients showed no excess of side effects.40 Side effectshave been noted with contrast agents but they are usually Indications for use of contrast in stress mild and transient (Table 1). However, serious allergic reac- tions have been observed, at a very low incidence (esti-mated to be 1:10 000). Table 5 lists mortality observed When two or more endocardial border contiguous segments during usage of competing investigations.41 Therefore, the of LV are not well visualized in order to: evidence shows that contrast echocardiography is very safein clinical practice. Except for SonoVue, both Optison and † To obtain diagnostic assessment of segmental wall motion Luminity may be used in acute coronary syndromes (ACS).
and thickening at rest and stress The contraindication on the use of contrast agents (Definity † To increase the proportion of diagnostic studies and Optison) in acute cardiac conditions was recently † To increase reader confidence in interpretation R. Senior et al.
Imaging modalities Power Doppler ultraharmonics Very sensitive for detection of Cannot assess wall motion Wall motion can be assessed Less sensitive for detection Power pulse inversion Cadence pulse sequencing (or coherent contrast imaging) Imaging modalities Contrast administration High mechanical index imaging Infusion methodInfusion of ultrasound contrast agents requires an infusion Harmonic imaging has become the standard imaging tech- pump that is not limited by the detection of microbubbles, nique for native (tissue) echocardiography, although it was and which may be intermittently agitated to maintain het- originally developed to enhance the detection of contrast erogeneity of distribution of the microbubbles. Agitation agents (Table 6). In order to use it optimally for contrast can be performed manually by slowly rocking the pump to studies, the transmit power must be reduced from an MI and fro. A special infusion pump has been developed for .1.0 to 0.4–0.6. However, even this power level is still SonoVue, which provides constant agitation. The pump can relatively high and can cause destruction of the contrast in be prepared in a few minutes prior to the study while the the nearfield of the transducer as well as create confounding patient undresses or during the baseline echo examination.
tissue signals in the myocardium, which impair the delinea- By an alternating rotating action the contrast agent is agi- tion of the endocardium.
tated preventing bubbles separating and floating to thesurface. The pump is then kept in a stand-by mode. Thepump is started by the sonographer using a remote control Low power imaging and no additional staff is needed. Although the pump pro- For clinical studies, the newer contrast-specific imaging vides the possibility of an initial small bolus, a constant infu- modalities (Pulse inversion Power Modulation and Cadence sion of Sonovue 0.8 mL/min from the start is usually Pulse Sequencing) are preferable. This low-power (‘Low satisfactory and need not be changed in the majority of MI') contrast-specific imaging technology provides the best patients. In contrast to a bolus injection, a continuous infu- LV opacification (homogeneous contrast, excellent endocar- sion over a short time provides stable conditions to acquire dial border definition). Because of the low transmit power, loops from different scanplanes and provides a steady-state less contrast is needed compared with standard real-time level to quantitatively assess myocardial perfusion. During harmonic imaging. In addition, myocardial opacification, stress echocardiography, the infusion can be stopped at which allows assessment of perfusion, can be studied simul- any time and resumed when needed. Between infusion taneously. Thus, perfusion can be assessed without pro- periods, the contrast agent is gently agitated. The contrast longation of the LVO contrast study and without increasing infusion is connected through a three-way-tap or small bore the amount of contrast agent infused. Scanning with the Y connector at the IV cannula, permitting the simultaneous new low-power contrast-specific imaging modalities for the infusion during dobutamine stress echocardiography.
detection of myocardial perfusion is an ‘off-label' appli-cation, as none of the currently available contrast agents have been approved for this indication. It should be noted, It is also possible to use slow bolus injections (0.2 mL) of however, that because the real-time Low MI modes transmit all agents (Sonovue, Luminity, and Optison) followed by multiple pulses down each image scan line, relatively low slow 5 mL saline flush over 20 s. However, these are not as frame rates may result, which are not optimal for wall controllable or reproducible as infusion.
motion assessment. This may be usually overcome by nar-rowing the sector width until the frame rate is at least25 Hz that is preferable for wall motion assessment during Myocardial contrast echocardiography Physiologic basis of myocardial contrast Low MI contrast-specific techniques display the contrast within the cavities of the heart and, because contrast micro-bubbles are red blood cell tracers, they accurately display The predominant (90%) component of myocardial blood the myocardial blood within the intramyocardial vessels.
volume resides within the capillaries.43 The myocardial The blood volume within the myocardial vessels comprises signal assessed visually as contrast intensity reflects the con- only 7% of the myocardium. Therefore, the myocardial opa- centration of microbubbles within the myocardium.44 When cification is always much less intense than the cavity opaci- the entire myocardium is fully saturated during a continuous fication, providing an excellent contrast for endocardial infusion of microbubbles, the signal intensity denotes the delineation. The myocardial contrast is also very useful for capillary blood volume. Any alteration of signal in such a assessing thickening of the myocardium and myocardial situation must, therefore, occur predominantly from a change in capillary blood volume. Furthermore, it has Evidence-based recommendations by EAE on contrast echocardiography been shown that following destruction, or depletion, of perfusion techniques for assessment of CAD. Concordance between MCE and SPECT has been demonstrated in many imaging, replenishment of contrast within the myocardium studies during rest or stress (Table 7).46–54, A meta-analysis can be observed.44 The capillary blood velocity is 1 mm/s of eight studies comparing the sensitivity and specificity of with an ultrasound beam elevation of 5 mm. Thus, it takes MCE with those of SPECT/dobutamine stress echocardiogra- 5 s for complete replenishment of the myocardium. Any phy for the detection of CAD showed equivalent results.55 In decrease in myocardial blood flow (MBF) prolongs replenish- a recently concluded, first multicentre, international phase ment time in proportion to the reduction in MBF.45 Myocar- III trial comprising of 662 patients and with all images being dial perfusion is defined as tissue blood flow at the read off-site by independent readers, MCE was found to be capillary level. The two components of tissue blood flow are capillary blood volume and red blood cell velocity. As (Figure 1).56 Similar trial with SonoVue (PHOENIX) is under microbubbles have been shown to be red blood cell flow way. Taken as an aggregate of published studies, the sensi- tracers, the product of peak microbubble intensity (repre- tivity and specificity of MCE for the detection of CAD is 83 sentative of myocardial blood volume) and their rate of and 80%, respectively (Table 8). However, it needs to be appearance (representative of blood velocity) equals emphasized that training and expertise are required to MBF.45 Therefore, myocardial contrast echocardiography achieve such results.57 (MCE) can detect capillary blood volume and, by virtue of Myocardial contrast echocardiography also provides incre- its temporal resolution, can also assess MBF. This imaging mental prognostic value over and above wall motion assess- technique of ‘destruction (or depletion) and replenishment' ment in patients with stable CAD during dobutamine stress requires the delivery of a series of high-energy ultrasound echocardiography.58 Patients with normal perfusion have a pulses to destroy (deplete) microbubbles in the myocar- better outcome than patients with normal wall motion, dium. Ultrasound imaging is then continued either intermit- which underscores the value of incorporating MCE in stress tently (during high-power imaging) or continuously (during low-power imaging) to observe contrast intensity and micro-bubble velocity.
Detection of acute coronary syndrome Detection of coronary artery disease The current diagnosis of ACS relies on clinical history, elec-trocardiography, and cardiac markers of necrosis. It has At rest, normally perfused myocardium demonstrates been shown that these parameters alone could detect appearance of contrast within five cardiac cycles during a 30% of ACS when the patient presents in the emergency destruction/replenishment acquisition; after stress, this is department.59 In a large multicentre study, performance reduced to two cardiac cycles, due to increased MBF.
of MCE improved the detection of ACS over and above clini- A delayed contrast appearance due to reduced blood flow cal, ECG, and biochemical markers at the time of presen- velocity and reduced contrast intensity due to decreased tation with chest pain and was equivalent to SPECT for capillary blood volume forms the basis for detection of risk stratification of these patients.60 However, MCE is the only technique that allows immediate simultaneous tomography (SPECT) using radionuclide agents such as assessment at the bedside of wall motion and perfusion 99mTc and 201Tl are now the most widely used myocardial and, in this regard, it offers a unique role in the diagnosis Concordance of myocardial contrast echocardiography and single-photon emission computed tomography for detection of significant coronary artery stenosis in patients with suspected coronary artery disease Percentage concordance (kappa) Wei et al., 200349 Olszowska et al.51 73–91 (0.4–0.8) Korosoglou et al.54 Overall mean [95% CI] Values are expressed as concordance and agreement (kappa).
AII, accelerated intermittent imaging; HPD, harmonic power Doppler; IPI, intermittent pulse inversion; PPI, power pulse inversion; RTI, real-time imaging; SPECT, single-photon-emission computed tomography; THI, triggered harmonic imaging; UN, unknown.
Adapted from Bhatia and Senior.104 R. Senior et al.
of ACS. Studies have also reported high sensitivities with Detection of myocardial viability MCE to detect ACS compared with standard echocardiogra-phy and SPECT.61,62 In a recent study of over 1000 patients, Microvascular integrity is a pre-requisite for the sustenance assessment of resting perfusion and function with MCE has of myocardial viability in dysfunctional segments.66 Peak been shown to be a powerful predictor of outcome, over contrast intensity, a measure of capillary blood volume cor- and above clinical ECG and troponin assessment of patients relates with microvascular density and capillary area, and is presenting to emergency department with suspected CAD.63 inversely related to the collagen content.67 Experimental Patients who demonstrated normal function and perfusion at models have established that contrast defect size assessed rest demonstrated excellent outcome.64 Moreover, stress 10–15 s after contrast administration, corresponded to MCE may be used to safely assess prognosis in patients infarct size.68,69 In humans, contrast defect intensity and with significant cardiac risk factors presenting with chest degree of reduction of resting MBF after intravenous con- pain, but a negative 12-h troponin and non-diagnostic trast administration predicted transmural extent of necrosis ECG. In these patients, a negative stress MCE result pre- assessed by late gadolinium CMR imaging.70,71 The ability of dicted an excellent prognosis.65 MCE to predict functional recovery is comparable with thatof cardiac MRI.70 Because contractile response with dobuta-mine depends not only on microvascular integrity (henceconservation of contractile protein) but also on MBFreserve, dobutamine stress echocardiography may be lesssensitive than techniques that assess microvasculaturedirectly (MCE) for the detection of hibernating myocar-dium.71,72 Therefore, MCE may be particularly useful infurther evaluation of myocardial viability in dobutaminenon-responsive myocardium.73 At least two studies indicatedthat MCE has superior sensitivity and equivalent specificitycompared with dobutamine echocardiography and hasequivalent sensitivity and superior specificity comparedwith SPECT imaging for the detection of hibernating myocar-dium.72,74 Tables 9–11 summarizes the accuracy of MCE forthe prediction of myocardial viability. Recent studies havealso shown that among all the clinical, ECG, and angio-graphic parameters of reperfusion after AMI, contrast per- Multi-reader receiver operating characteristics. Values fusion is the only independent predictor of reperfusion.75–77 for each blinded reader from RAMP-1 and -2 trials. Modality-specific With accumulating evidence of its prognostic value for the curves were extrapolated to the theoretical minimum and maximum detection of myocardial viability over and above clinical values. AUCs were 0.72 for both PSE and SPECT.
Accuracy of myocardial contrast echocardiography for the detection of coronary artery disease Patients undergoing coronary angiography Elhendy et al.107 Jeetley et al.108 Karavidas et al.109 Korosoglou et al.54 Olszowska et al.51 Quantitative 79–82 RT imaging 64TR imaging 41 RT imaging 92TR imaging 96 Aggeli C et al.41 Evidence-based recommendations by EAE on contrast echocardiography Accuracy of resting intravenous myocardial contrast echocardiography for the prediction of myocardial viability No. of patients (n ¼ 736) Swinburn et al.117 Janardhanan et al.70 Hickman et al.120 Janardhanan et al.121 Bolognese et al.76 MCE, myocardial contrast echocardiography.
clinical study by the same group, they showed that assess- Interpretation of resting contrast echo studies ment of MBF during hyperaemia provided an accurateassessment of coronary flow reserve.82 This was sub- Myocardial contrast Diagnostic confidence sequently replicated by other authors.83 Indeed, Vogelet al.84 demonstrated that MBF assessed by MCE at rest and during hyperaemia closely correlated with MBF assessed Stunning, hibernation by positron emission tomography. Further studies in various cardiovascular disease conditions showed that coronaryflow reserve assessed by MCE can accurately assess boththe presence and severity of flow-limiting CAD.85–88 Thisassessment can be performed using both low and high MI Interpretation of stress contrast studies imaging techniques. The myocardium is first cleared ofmicrobubbles during high MI imaging and subsequent replen- Diagnostic confidence ishment is assessed in time (Figure 3). Myocardial blood flow which is the product of peak contrast intensity and myocar-dial flow velocity is obtained. It is obtained in each of the myocardial segments in the apical views (preferably avoid- High perfusion defect often depicts ing the basal segments—see below). The MBF obtained in extent of ischaemia better each segment can then be collapsed into the three vascular May be artefact, but if in centre of territories. The process is repeated during stress myocardial plane cardiomyopathy imaging preferably vasodilator stress. The ratio of the peak MBF and that of resting flow indicates coronary flow reserve.
The ratio of peak myocardial blood velocity (b/rest b) alsoprovides a robust estimate of coronary flow reserve.82 markers and LVEF, MCE is evolving as a useful bedside tech-nique that may be used as first line investigation for the Limitations of myocardial contrast assessment of myocardial viability.77–80 Algorithms for the use of MCE after AMI are shown in Figure 2A and B.81 Myocardial contrast echocardiography, like all other tech-niques, requires training and understanding of the technol- Assessment of coronary flow reserve by ogy. The signature of MCE is the result of interaction myocardial contrast echocardiography between the microbubbles and ultrasound power. Thus, vari-ation in concentration of microbubbles with each adminis- The first experimental study by Wei et al.45 established tration may influence the contrast intensity. Ultrasound quantitative evaluation of MBF using MCE. In a subsequent power is not uniform in the field of view and this may

R. Senior et al.
(A) Schematic diagram for the proposed role of myocardial contrast echocardiography in assessment of patients in the acute phase of STEMI. (B) Schematic diagram for the proposed role of myocardial contrast echocardiography in assessment of patients with recent STEMIfollowing reperfusion Hayat and Senior.81 affect the estimation of myocardial blood volume and vel- MCE readers was non-inferior and similar to that of SPECT ocity. Because ultrasound power is weakest in the far field, contrast intensity may be falsely reduced at the bases of theheart. Similarly, as the power of ultrasound is the strongestin the near-field, and apical destruction of contrast may Protocols for myocardial contrast result in false perfusion defects. However, recent advance- ment in technology and understanding of microbubble and Exercise stress protocol ultrasound interaction has improved interpretation signifi-cantly. In a recently concluded multicentre trial involving The protocols are the same as for native stress echocardio- 27 centres in USA and Europe, diagnostic images could be graphy.89 Recordings are performed at rest according to obtained in 99% of patients. The reproducibility of multiple the protocol for rest echocardiography (Figures 4 and 5).

Evidence-based recommendations by EAE on contrast echocardiography Quantification of myocardial blood flow by myocardial contrast echocardiography.
Further image acquisition is performed immediately after echocardiograms are acquired at rest (before infusion) and treadmill exercise, upright or supine bicycle ergometry.
2 min after completion of infusion. The same infusion line Because ischaemia-induced wall motion abnormalities may is used to administer the contrast agent and the vasodilator.
resolve quickly, post-treadmill exercise imaging should be Alternatively, an infusion of adenosine 140 mg/kg/min (half- accomplished within 60–90 s of termination of exercise.
life 4–10 s) can be used. The contrast echocardiograms are Therefore, it is necessary to inject the bolus (if only wall acquired prior to infusion and again during the infusion at motion is assessed) or start the infusion (ideal for assessing 3 min. Usually, all the three apical views + available para- perfusion) of contrast before the patient terminates the sternal views can be acquired within the subsequent exercise. After application of the contrast agent, the 3 min, resulting in a total adenosine infusion time of 6 min patient should be asked to continue the exercise for at (Figure 7). For both vasodilators, a three-way tap or small least 20 s, before laying down for image acquisition.
bore Y connector is useful to connect the vasodilator infu-sion lines and contrast infusion pump.
Dobutamine stress echocardiography The protocol for native dobutamine stress echocardiography Myocardial contrast echocardiography is described elsewhere except apical views are acquired first for myocardial viability (Figure 6).89 Resting image settings should be optimized and Rest contrast images are acquired as described previously.
resting contrast echocardiogram views should be obtained However, when real-time imaging protocol is used, it is according to the criteria described previously. The same important to acquire at least 15 sc cycle post-flash for views are acquired at an intermediate stage (70% of the optimal assessment. It has been shown that both the pre- maximum age predicted heart rate) and at peak stress (85% sence of homogenous contrast uptake and, alternatively, of the maximum age predicted heart rate). Contrast can be the absence of contrast uptake are very accurate indicators administered as a bolus or as an infusion, as described pre- of the presence or absence of myocardial viability, respect- viously. If the SonoVue-infusion pump or Luminity drip is ively. It is, however, important to exclude apical and basal used, infusion is needed only while acquiring the images.
artefacts before concluding that there is absent contrast Prior to acquisition of the peak stress loops, the contrast infu- uptake. High MI imaging should also include imaging up to sion is started and the dobutamine infusion is stopped. Within 15 s intermittent image acquisition. The transmit focus 30 s, there is sufficient contrast enhancement and the peak should be moved towards the apex to confirm an apical per- contrast images are acquired in the apical views (and para- fusion defect when suspected. A thin and scarred (bright) sternal views if of sufficient quality). Image acquisition at myocardium of ,5 mm in size indicates non-viable tissue stress is not different from acquisition at rest except when and it is unnecessary to assess perfusion in these segments.
using triggered imaging. A 1:1 trigger interval should beused at peak stress whereas at rest 1:4 is useful. Adjustment of the time delay of the trigger may be necessary at peakstress to allow for the increased heart rate.
Lefrt ventricular function and regional wall motionVisual analysis of LV function is performed in all patientsaccording Vasodilator stress Vasodilator stress is the best stress modality enhancement of the epicardial vessels helps in judging for perfusion imaging wall thickening as well as inward motion of the myocardium.
An amount of 0.56 mg/kg of dipyridamole (half-life 30 min) Contrast images are ideal for measuring LV volumes and LVEF. The post-flash (destruction) images provide the best R. Senior et al.
Protocol for myocardial contrast echocardiography. Protocol 1.
contrast between myocardium and the LV cavity. Manual Myocardial perfusion tracing on still frames to obtain LV volumes and ejection Although there is growing evidence of the usefulness of fraction is easy and quick. Therefore, in every contrast quantitative analysis,92 myocardial contrast signals are cur- study, these measurements should be obtained. The tools rently judged using visual assessment.
for automatic assessment of LV borders (such as colour Normal myocardial perfusion is displayed by homogeneous kinesis), as well as 3D echocardiographic volumetric assess- contrast enhancement at rest 5 s after flash (Low MI ments with contrast are currently being investigated in clini- imaging) or high MI imaging and a quick replenishment at cal trials and may be useful clinical tools in the future.90,91 stress (within 2 s).

Evidence-based recommendations by EAE on contrast echocardiography Protocol for myocardial contrast echocardiography. Protocol 2.
have the same or worse imaging conditions. The diagnosticconfidence of an observed perfusion defect increases when Dobutamine stress contrast protocol.
two contiguous segments fail to exhibit contrast enhance-ment. A contrast defect is usually seen first in the subendo- Perfusion defect by myocardial contrast cardium and does not extend over the full thickness of the myocardium. The specificity for the detection of a perfusion A visually evident contrast defect is considered present defect is decreased in the absence of at least some contrast when there is a relative decrease in contrast enhancement signal in the epicardium; full thickness defects in which both in one region compared with other adjacent regions that endocardium and epicardium are absent are more likely to R. Senior et al.
be due to artefact such as attenuation or rib shadowing.
intervention. Combined assessment of wall motion and per- Basal lateral and anterior walls quite often cannot be fusion can also help to increase the diagnostic confidence of assessed because of these limitations. However, there is usually enough adequate information in other segments accompanied by a perfusion defect suggests flow-limiting in the LAD or RCX perfusion territories to permit the CAD. A new wall motion abnormality without a correspond- assessment of adequacy of perfusion by coronary artery ing perfusion defect may suggest cardiomyopathy.
Training and accreditation Fixed vs. reversible perfusion defect Both physicians and cardiac sonographers must have Fixed perfusion defects are visible at rest and stress. Revers- acquired basic echocardiography training and preferably ible defects are best seen early after the flash (during the accredited in echocardiography before using contrast first 2 cardiac cycles using real-time imaging) or with low agents. Those planning to use contrast agents during stress trigger rate (1:1 using high power triggered imaging).
echocardiography must be accredited or at least must Reversible defects suggestive of CAD are characterized by have undergone equivalent training in stress echocardiogra- delayed subendocardial replenishment and subendocardial phy. Beyond these trainings in rest and stress echocardiogra- hypoenhancement. With longer replenishment time (low MI phy, the use of contrast agents requires a level of experience imaging) or increased trigger intervals (high MI imaging), and performance, initially under guidance or supervision.
reversible defects often decrease in size or fill in.
Physicians, sonographers, and nurses alike should be compe- When assessing for potential perfusion defects, it is tent in the administration of contrast agents, should be crucial to avoid either oversaturation with contrast, or aware of the indications and contraindications, and should alternatively, inadequate concentration of contrast. Subtle be able to manage adverse events. It is encouraged that per- subendocardial defects may be obscured by excess contrast.
sonnel involved in contrast use should attend courses, etc.
These may be revealed by a reduction in contrast infusion to learn and familiarize themselves with the use of contrast, rate or further bubble destruction with additional intermit- performance, and interpretation of contrast-enhanced tent high power frames. On the other hand, inadequate con- images. This is particularly important if the echo team is trast concentration will obviate the detection of normally contemplating using contrast for assessment of perfusion perfused and relatively underperfused regions.
also.127,128 The echo team should seek guidance from thelocal echocardiography society of institutional director todetermine ways to set up myocardial perfusion programme.
Integrating wall motion findings and judgment It cannot be emphasized more that experience with contrast agent for LVO is a prerequisite for moving on to assess per- During rest echocardiography (Table 10) fusion and function with contrast agents.
This may be particularly useful when the assessment of LVwall motion is difficult or dubious at rest. Probably, the most important situation where perfusion imaging makes adifference is in akinetic areas (Table 7). Before one tries Contrast echocardiography significantly improves the image to assess myocardial contrast enhancement, it is important quality during rest and stress echocardiography and at the to look at myocardial thickness that often can be seen same time provides additional information on myocardial very well during infusion of contrast. When analysing loops perfusion. Contrast echocardiography reduces the need for obtained with real-time imaging, judgement of wall additional, costly, and more hazardous tests and, impor- motion and myocardial perfusion is often combined. A sub- tantly, spares the patient further invasive investigations.
endocardial perfusion defect makes a wall motion abnormal- Thus, contrast echocardiography provides a safe and com- ity much clearer and vice versa. Thus, assessment of prehensive assessment of cardiac structure, function, per- myocardial contrast often helps by increasing the diagnostic fusion, and coronary flow reserve at the bedside.
confidence of dubious wall motion analysis. In a restingstudy, a perfusion defect can be due to ischaemia with aflow limiting coronary stenosis at rest, a scar, or an artefact.
Conflict of interest: R.S. received research support from Bracco, Artefacts are most likely to occur in the basal lateral and Acusphere. M.M. has received research support from Bracco, Acu- anterior walls and can easily be detected by the typical cri- sphere, Philips, GE, Siemens; Speaker's Bureau: Philips, Siemens.
teria of attenuation and shadowing, in the presence P.N. has received research grants from Bracco and Medtronic. H.B.
acts as a consultant for Lantheaus, Bracco, POINT, Acusphere and of normal myocardial wall thickening. Other discrepant has research grants from Phillips, Sonosite, Siemens, Toshiba.
findings between wall motion and myocardial contrastenhancement occur with stunning and hibernation. Both con-ditions can be suspected when reduced wall motion and good contrast enhancement are found in a resting perfusion study.
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Effect of divalproex on brain morphometry, chemistry, and function in youth at high-risk for bipolar disorder: a pilot study

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 19, Number 1, 2009 ª Mary Ann Liebert, Inc.Pp. 51–59DOI: 10.1089=cap.2008.060 Effect of Divalproex on Brain Morphometry, Chemistry, and Function in Youth at High-Risk for Bipolar Disorder: A Pilot Study Kiki Chang, M.D., Asya Karchemskiy, M.S., Ryan Kelley, B.A., Meghan Howe, M.S.W., Amy Garrett, Ph.D., Nancy Adleman, B.S., and Allan Reiss, M.D.


Author's personal copy Available online at www.sciencedirect.com Hormones and Behavior 53 (2008) 192 – 199 Rapid effects of estradiol on male aggression depend on photoperiod in reproductively non-responsive mice Brian C. Trainor a,b,⁎, M. Sima Finy b, Randy J. Nelson b a Department of Psychology, University of California, Davis, CA 95616, USA b Departments of Psychology and Neuroscience, Institute for Behavioral Medicine Research, Ohio State University, Columbus, OH 43210, USA