Myocardial contrast echocardiography in routine clinical practice

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Myocardial contrast echocardiography in routine
clinical practice
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WHY ?
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Clinical and economic outcomes assessment with
MCE, Leslee et al, Heart 1999.
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• Principles of Contrast echocardiography
• Blood appears black on conventional two
  dimensional echocardiography, not because blood
  produces no echo, but because the ultrasound
  scattered by red blood cells at conventional
  imaging frequencies is very weakseveral thousand
  times weaker than myocardiumand so lies below
  the displayed dynamic range

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• Contrast ultrasound results from scattering of
  incident ultrasound at a gas/liquid interface,
  increasing the strength of returning signal.
• However, the bubble/ultrasound interaction is
  complex.
• Understanding this interaction is key to
  performing, understanding, and interpreting a
  contrast echo study.

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• Physics in ultrasound
• Unlike solid tissue, gas bubbles have acoustic
  properties that vary with the strength of the
  insonating signal. When insonated ----gt gas
  bubbles pulsate-----gt with compression at the
  peak of the ultrasound wave and expansion at the
  nadir.
• An ultrasound beam with a frequency of 3 MHz,
  will result in bubble oscillation three million
  times per second AND hence are several million
  times more effective at scattering sound than red
  blood cells. With this movement, sound is
  generated and, combined with that of thousands of
  other bubbles, results in the scattered echo from
  the contrast agent.
• Characterising this echo, from that of tissue,
  form the basis of contrast echocardiographic
  studies.

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• It is a remarkable coincidence that gas bubbles
  of a size required to cross the pulmonary
  capillary vascular bed (15 mm) resonate in a
  frequency range of 1.57 MHz, precisely that used
  in diagnostic ultrasound.

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• At low poweroutput (PO) settings, there is mostly
  a linear response (fundamental enhancement) with
  some generation of harmonic frequencies.
• As the PO is increased, the bubbles generate more
  nonlinear resonance and thus generate greater
  harmonic frequencies.
• At a high power setting, fracture and destruction
  of the microbubble occur, allowing the air or gas
  inside to be released.

(lt100 kPa)
(100 kPa1 Mpa)
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• Contrast imaging requires ultrasound machine
  settings to be optimised. Generally, this
  requires variation in the system power output,
  indicated on clinical systems as the mechanical
  index (MI) (most important parameter) The MI is a
  unit-less number that serves as an indicator of
  the nonthermal bioeffects.
• This is an estimate of the peak negative pressure
  within insonated tissue defined as the peak
  negative pressure divided by the square root of
  the ultrasound frequency.
• Display of the MI was made mandatory in the USA
  as a safety measure, to enable an estimate of the
  tissue effects of ultrasound exposure to be made.
  As this also reflects the mechanical effect of
  ultrasound on a contrast bubble, this has proved
  useful in developing machine settings for
  contrast ultrasound.

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• Standard clinical echocardiography imaging
  utilises an MI of around 1.0, but a lower
  setting, around 0.5, is usually optimal for left
  ventricular opacification.
• To achieve myocardial perfusion imaging the
  extremes of power output are utilised
• high MI (gt 1.2) is used to achieve bubble
  destruction in power Doppler imaging, and
• ultra low MI (lt 0.1) required to induce linear
  oscillation of microbubbles required for real
  time myocardial perfusion imaging.

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Current generation of contrast agents comprises
small, stabilized, gas-filled microbubbles that
can pass through the smallest capillaries.

• Current microbubbles can be visualized within the
  left heart chambers after an intravenous
  injection for two reasons
• (1) they are smaller than red blood cells
  and so can pass through the pulmonary
  capillaries, and
• (2) they are stable, relative to time and
  pressure (they can persist long enough to travel
  through the pulmonary capillary bed, and they can
  withstand left-sided pressures).

The larger the microbubbles, the better the
contrast effect
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• The properties of the Air- filled microbubble are
  -
• a strong reflector of ultrasound and highly
  soluble
• But has low persistence and lacks stability
  because air diffuses out. This shrinking
  microbubble becomes less and less reflective.
• WHEREAS
• Gases are of high molecular weight are-
• not very soluble hence stable with longer
  persistence.
• Persistence prolongs contrast effect so that
  assessment of left ventricular borders and wall
  motion can be made.

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• The ultrasonic characteristics depends on -
• a) size of the bubble
• b) composition of the shell and the gas in the
  shell.
• The outer shell of the microbubbles is composed
  of many different substances, including
• albumin, polymers, palmitic acid,or
  phospholipids.
• This composition determines its elasticity, its
  behavior in an ultrasonic field, and the methods
  for metabolism and elimination.
• In general, the stiffer the shell, the more
  easily it will crack or break with ultrasonic
  energy. Conversely, the more elastic the shell,
  the greater its ability to be compressed or
  resonated and to produce a nonlinear backscatter
  signature.

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• The major technical difficulties in using
  contrast agents for left ventricular
  opacification are
• the need to resonate but not burst microbubbles
  and
• to maintain adequate bubble concentration within
  the cavity.
• injection of a sufficient concentration of
  microbubbles and
• the proper ultrasonographic equipment settings
  to optimize image quality.
• Inadequate bubble concentration, causes less
  opacification of the chamber, which was a
  difficulty with first-generation agents because
  of excessive bubble destruction when insonified
  with ultrasound.
• Left ventricular opacification requires a long
  duration of the contrast effect for the
  assessment of left ventricular borders in
  suboptimal patients both in rest and under
  stress.
• Contrast agents that are easily destroyed will be
  useful in myocardial perfusion studies.

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• CONTRAST AGENTS FOR ULTRASOUND
• Initially contrast echocardiography utilised free
  air in solution but these large, unstable bubbles
  were not capable of crossing the pulmonary
  vascular capillary bed, allowing right heart
  contrast effects only.
• The first agents capable of left heart contrast
  after intravenous injection (first generation
  agents) were air bubbles stabilised by
  encapsulation (Albunex) or by adherence to
  microparticles (Levovist).
• Replacing air with a low solubility fluorocarbon
  gas stabilises bubbles still further (second
  generation agentsfor example, Optison, SonoVue),
  greatly increasing the duration of the contrast
  effect.
• Third generation agentsnot yet commercially
  availablewill use polymer shell and low
  solubility gas and should producemuch more
  reproducible acoustic properties.

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• PERFORMING A CONTRAST STUDY
• Bubbles are prone to destruction by physical
  pressure, hence requires meticulous attention to
  the preparation and administration.
• The agent should be prepared immediately before
  injection and vents used when withdrawing the
  agent into the syringe. Bubbles tend to float
  towards the surface and the contrast vial or
  syringe should be gently agitated each time fresh
  contrast administration is required.
• Injection through a small lumen catheter
  increases bubble destructiona 20 G or greater
  cannula should be used.
• Very small volumes of contrast are needed using
  second generation agents (lt 1 ml) and a flush is
  required by using a three way tap,with contrast
  injected along the direct path to minimise bubble
  destruction, and saline flush injected into the
  right angle bend.
• For myocardial perfusion work, infusion produces
  more reproducible results with the potential for
  quantification6 but brings its own problems.
  Bubbles in agents currently available are buoyant
  and will tend to rise to the surface of the
  syringe.
• Purpose designed infusion pumps which agitate
  contrast continuously are in development but not
  yet widely available.

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• A PFO is diagnosed if more than three
  microbubbles pass from right to left atrium
  within three cardiac cycles of right atrial
  opacification.
• Crude quantification is possible with
• a small shunt defined as 310 bubbles,
• a medium shunt 1020, and
• a large shunt gt 20 bubbles.
• An initial study should be performed during
  normal respiration, when the normal reversal of
  atrial pressure gradient in early systole may be
  sufficient to allow shunting if a large defect is
  present.

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LEFT VENTRICULAR OPACIFICATION

• Assessment of left ventricular (LV) systolic
  function is the most common indication for
  echocardiography. Accurate assessment and
  quantification is dependent on visualising the
  entire endocardium in cross section.
• Tissue harmonic imaging has greatly improved
  image quality and reduced the number of
  non-diagnostic studies.
• Contrast opacification of the left ventricular
  cavity enhances endocardial border definition and
  has been shown to increase diagnostic accuracy in
  suboptimal studies at rest and during stress.
• This is the major clinical use of left heart
  contrast echocardiography at present

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• Contrast echo is useful in the assessment of LV
  function in patients ventilated in intensive
  care, reducing the time required to obtain
  diagnostic information and obviating the need for
  trans-oesophageal echocardiography.
• While apical imaging is greatly enhanced,
  para-sternal views may deteriorate, at least
  initially,with contrast in the right ventricle
  attenuating visualisation of the left. For this
  reason, apical views should routinely be obtained
  first in any contrast study.
• LV opacification is also used to delineate LV
  anatomy, particularly apically, confirming
  pseudo-aneurysm, apical hypertrophy or
  ventricular non- compaction and demonstrating
  filling defects, typically apical thrombus.

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• MYOCARDIAL PERFUSION IMAGING
• Myocardial contrast echocardiography (MCE) is
  the imaging of a contrast agent within the
  myocardial capillary vascular bed is
  reproducible, real time, noninvasive assessment
  of myocardial perfusion during rest and stress,
  at the bedside and in the cardiac catheterisation
  laboratory.
• At present, MCE remains difficult and suboptimal
  imaging prohibits routine use.
• While LV cavity opacification with contrast can
  make a difficult study diagnostic, only those
  with high quality baseline B mode images are
  suitable for MCE with current equipment.
• Intravenous injection of contrast results in
  very low concentration of bubbles in the
  myocardium, with only 510 of cardiac output
  entering the coronary circulation. As more than
  90 of intramyocardial blood volume is within the
  capillary compartment, contrast bubbles are
  imaged at low velocity with slow replenishment
  following bubble destruction.

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• Dissolution and destruction of microbubbles by
  both intramural pressure and ultrasound exposure
  further limits any contrast effect. Thus,
  contrast specific imaging modalities must be
  used. Broadly, there are two approaches used to
  overcome the problems inherent in myocardial
  contrast perfusion imaging intermittent imaging
  and pulse inversion or power modulation imaging.
• Flash imaging, utilising a pulse of echo at high
  MI to destroy all microbubbles within the
  myocardium, combined with low MI real time MCE
  allows assessment of perfusion in real time .
  This technique can be used to quantify rate of
  bubble replenishment in the myocardium

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LVO PROTOCOLS FOR A BOLUS INJECTION OFCONTRAST
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• New possibilities have emerged with
  second-generation contrast agents containing high
  molecular- weight gases such as fluorocarbons
  (Optison, MBI/Mallinckrodt Sonazoid, Nycomed
  Amersham, Amersham, Bucks, U.K. and EchoGen,
  Sonus/Abbott, Seattle, WA, U.S.A.) or sulphur
  hexafluoride (SonoVue, Bracco, Milan, Italy).
• In a phase III multi centre trial that compared a
  first generation (Albunex) with a second
  generation (EchoGen) contrast agent demonstrated
  the superiority of fluorocarbon-containing
  microbubbles over sonicated human albumin for LV
  cavity opacification, endocardial border
  definition, duration of effect, salvage of
  suboptimal echocardiograms, diagnostic confidence
  and potential to influence patient management.

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• Reilly et al demonstrated that a second
  generation contrast agent could significantly
  improve the quality of echocardiograms in the
  intensive care unit. They evaluated wall motion
  analysis with standard fundamental
  echocardiography, harmonic echocardiography and
  contrast echocardiography. Wall motion was seen
  with greater confidence after contrast
  echocardiography.
• Another study, Kornbluth et al. in mechanically
  ventilated patients, showed the use of contrast
  was superior to tissue harmonic imaging for
  endocardial border delineation, wall motion
  scoring and quantification of ejection fraction.

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• In Stress echocardiography a sizeable proportion
  of patients can benefit from the additional use
  of contrast media to improve endocardial border
  detection.
• At peak exercise image quality is often low
  because of tachycardia. Only when endocardial
  borders are well delineated and reproducible can
  useful results be expected with stress
  echocardiography.
• The use of contrast during stress
  echocardiography in patients with suboptimal
  imaging may have a positive impact on cost it
  can indeed enhance diagnostic confidence in
  stress echocardiography, with improvement in
  image quality in approximately 50 of patients.
• In a group of poorly echogenic patients
  undergoing dopamine echocardiography,Voci et
  al.30 demonstrated that infusion of insonicated
  albumin provided adequate LV opacification in 90
  of patients, with significant reduction in
  inter-observer variability in ejection fraction
  measurements.

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• At present, the best solution for improving
  endocardial border visualization is a combination
  of intravenous contrast LV opacification and
  harmonic imaging.
• In a review of 200 patients referred for stress
  echocardiography, a combination of native tissue
  harmonic imaging and contrast application was
  used. The combination resulted in significantly
  better visualization of the endocardium as
  compared with fundamental contrast imaging, and
  an increased inter-observer agreement for border
  detection, which increased from 83 in
  fundamental mode without contrast to 95 with
  contrast native tissue harmonic imaging.

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• Contrast stress echocardiography, despite the
  added cost of the agent, can still provide a cost
  saving of 15, and accuracy and outcome
  assessment are similar to those of nuclear
  techniques.
• For conventional stress echocardiography, recent
  reports have documented that its diagnostic
  accuracy is similar to that of myocardial
  perfusion evaluation using nuclear techniques.
• Currently, if the patient does not have a good
  acoustic window then stress echocardiography
  should not be performed without contrast
  enhancement.
• The maximum yield of contrast enhancement has
  been demonstrated when approximately two to six
  segments are not satisfactorily delineated.

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Comparison of myocardial contrastechocardiography
with single-photon emissioncomputed tomography

• MCE may be compared with single-photon emission
  computed tomography (SPECT).
• Results of the earliest studies that compared MCE
  with SPECT were encouraging. However, larger
  clinical trials have shown that MCE, when
  compared with SPECT, has a good specificity but
  relatively low sensitivity. The question of
  training is important.
• The study conducted by Marwick et al., which
  involved centres for which MCE was not initially
  a routine investigation, showed that performance
  and interpretation of perfusion echocardiography
  requires special expertise.
• The recent introduction of new techniques such as
  harmonic power Doppler resulted in good
  concordance between MCE and SPECT.
• A study conducted by Rocchi et al revealed
  excellent sensitivity and specificity (82 and
  95, respectively) in detecting viable myocardium
  in segments supplied by infarct-related arteries,
  but more studies are needed to establish the
  value of MCE.

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No-reflow phenomenon

• Restoration of epicardial flow in the
  infarct-related artery, as indicated by
  Thrombolysis in Myocardial Infarction (TIMI)
  grade 3 flow, does not necessarily imply normal
  flow at the level of the microcirculation. The
  no-reflow phenomenon was initially observed in
  the 1970s by Kloner et al and was subsequently
  confirmed clinically by MCE, which can define the
  presence and extent of flow at the level of the
  microcirculation.
• In the 39 patients with acute myocardial
  infarction (AMI) before and immediately after
  successful coronary recanalization studied by Ito
  et al. up to 23 of patients showed lack of
  microvascular reperfusion (or no-reflow)
  despite a fully patent infarct-related artery.
• In another study of 86 patients who underwent
  coronary revascularization and MCE with
  intra-coronary application of contrast, reduced
  myocardial contrast effect was demonstrated in
  all patients with TIMI grade 2 flow. In 16 of
  patients with TIMI grade 3 flow, reduced
  myocardial reperfusion was seen. Those patients
  had a reduced wall motion score and ejection
  fraction at 28 days as compared with patients
  with normal myocardial perfusion by MCE, and
  their outcome was similar to that of patients
  with TIMI grade 2 flow.
• These findings demonstrate significant
  correlation between myocardial perfusion and LV
  function.

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• Porter and coworkers demonstrated that adequate
  perfusion imaging may be achieved with
  intravenous injection of perfluorocarbon-exposed
  sonicated dextrose albumin. In one study,
  conducted in 45 consecutive patients 24 16
  days after an AMI, 29 of the patients with TIMI
  grade 3 flow showed evidence of contrast defect.
  The patients had a significant increase in both
  end-systolic volume and wall motion score index
  at follow-up (4 weeks after myocardial
  infarction).
• In another study, in which power Doppler harmonic
  imaging was used for identification of
  reperfusion after AMI, showed very good
  sensitivity and specificity (82 and 95,
  respectively) of this technique in depicting
  perfusion status in segments supplied by infarct-
  elated arteries.

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• Moreover, the accuracies of power Doppler
  harmonic imaging MCE and SPECT were similar (90
  and 92 on segmental basis, and 98 versus 98 on
  coronary artery territory basis), which
  apparently provides evidence for the superiority
  of this technique in the assessment of myocardial
  perfusion over the techniques that are based on
  greyscale modalities.
• There was a correlation between perfusion defects
  and functional recovery after 6 weeks, yielding
  prognostic information for the recovery of
  ventricular function and allowing differentiation
  between stunned and necrotic myocardium.
• MCE has great potential in this context because
  it offers the unique possibility of exploring the
  integrity of the microcirculation in vivo, a
  fundamental prerequisite for myocardial viability

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Acute coronary syndromes

• In the emergency room, detection of normal
  perfusion may allow safe discharge and may avoid
  the costs of unnecessary hospitalization.
• In the case of detectable perfusion defect
  without previous myocardial infarction, an acute
  coronary syndrome may be diagnosed and, depending
  on the extent of this defect, a conservative or
  aggressive diagnostic approach may be applied.
• In the situation of established AMI, Agati et
  al. compared the infarct size and microvascular
  perfusion 1 month after AMI in relation to the
  applied therapy primary coronary angioplasty or
  thrombolysis. That study showed that, after
  successful recanalization of the infarct related
  artery, primary angioplasty is more effective
  than thrombolysis in preserving microvascular
  flow and preventing extension of myocardial
  damage.
• MCE is a simple bedside method to monitor the
  success of therapy, and may help in the
  decision-making process (i.e. whether to proceed
  to coronary angiography and rescue interventions
  when thrombolytic therapy fails to achieve full
  reperfusion).

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Chronic ischaemic heart disease

• Currently available methods for detection of
  myocardial ischaemia have several limitations.
• Stress ECG is positive in only 50 patients with
  single vessel disease (stenosis gt70) and
  provides limited information on the extent of
  ischemia. Stress echocardiography is currently
  the most important diagnostic method. The
  sensitivity and specificity for CAD are between
  80 and 90. However, flow must be reduced to 50
  in at least 5 of the myocardium to detect new
  wall motion abnormalities. Additionally, stress
  echocardiography cannot be used when an unstable
  process is suspected.
• Myocardial scintigraphy is currently the only
  well established method that directly addresses
  myocardial perfusion, but this technique is not
  as widely available as echocardiography it is
  more expensive and has a lower spatial
  resolution.
• The potential value of MCE in the diagnosis,
  treatment, follow-up and outcome prediction of
  CAD is clear, especially with the fact that MCE
  can identify very early stages in the ischaemic
  cascade.

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• In a study conducted by Meza et al. MCE had a
  good negative predictive value (gt80) for
  estimating attenuated regional function 60 days
  after surgery.
• In a study that assessed the ability to detect
  angiographically significant CAD with accelerated
  intermittent imaging after intravenous contrast
  administration during stress echocardiography, an
  agreement between regional perfusion and
  quantitative angiographic findings was found in
  217 of the 270 regions analyzed (k 061, 80
  agreement, gt50 stenosis).
• The greatest incremental benefit of accelerated
  intermittent imaging versus wall motion was
  gained with dobutamine-induced stress. The
  contrast studies depicted 90 of the regions
  supplied by a vessel with more than 50 stenosis,
  whereas wall motion analysis depicted only 32 (P
  0001).
• In a study by Porter et al. accelerated
  intermittent imaging allowed real-time assessment
  of myocardial blood flow and wall thickening
  simultaneously, though this requires further
  assessment and validation.

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Collateral blood flow assessment

• The extent of coronary collateral circulation can
  determine the percentage of necrotic myocardium
  during AMI
• In the study conducted by Sabia et al. MCE could
  define the percentage of the risk area provided
  by collaterals, and there was only partial
  correlation with angiographic degree of
  collaterals.
• In the study conducted by Mills et al.in animals,
  those investigators demonstrated the possibility
  of following the development of coronary
  collateral circulation using serial MCE
  examinations. This method may permit
  investigation of the physiology of collateral
  development in vivo and may allow the results of
  therapeutic angiogenesis to be monitored.

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• Recent advances in MCE
• Transthoracic echocardiography following contrast
  injection helps to detect LV thrombi .
• With high-resolution Doppler echocardiography
  coronary vasomotion and flow reserve from the
  chest without the need for contrast agents can be
  measured.
• Development of tissue specific microbubbles,
  which would allow drug delivery or clot
  identification.
• Finally, the development of bubbles with a very
  narrow distribution may open the possibility to
  measure intra-cavitary pressures in a
  non-invasive manner.

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Assessment of Myocardial Postreperfusion
Viability by Intravenous Myocardial Contrast
Echocardiography Analysis of the Intensity and
Texture of Opacification, Koji Ohmori, MD,
Circulation April 17, 2001

• examined the relationship between the
  opacification pattern produced by a new
  intravenous dodecafluoropentane contrast agent
  and histological evidence of necrosis or
  viability after reperfusion of coronary
  occlusion.

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• This is the first application of echo texture
  analysis to quantify altered opacification
  pattern produced by intravenous MCE in infarcted
  segments after reperfusion.
• Thus, these data suggested that texture
  characterization of the contrast opacification
  pattern has the potential to complement
  conventional intensity measurements of
  intravenous MCE in determining myocardial
  viability after reperfusion.

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Identification of Hibernating Myocardium With
Quantitative Intravenous Myocardial Contrast
Echocardiography Comparison With Dobutamine
Echocardiography and Thallium-201 Scintigraphy
Sarah Shimoni, Circulation February 4, 2003
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Conclusion

• Implementation of contrast into clinical practice
  will increase the diagnostic power of
  echocardiography, providing complex structural
  and functional information in a fast one stop
  shop examination, without a large increase in
  overhead costs.
• However, much work needs to be done to
  understand the behaviour of bubbles to improve
  image quality and to implement new solutions into
  echocardiographic equipment.
• However, rigorous cost-effectiveness analyses
  have not been done, particularly in perfusion
  studies. In an era of poor resources, it is
  impossible to overlook economic constraints.
• On the basis of current evidence, it appears that
  contrast echocardiography can improve health
  outcomes at reasonable cost and may represent
  good value for money, even if it is a
  cost-increasing technology.
• This aim will be achieved once echocardiography
  is refined to the point that it can offer a
  high-quality, conclusive result in almost every
  examination, and provide anatomical, perfusion
  and functional data all in one examination. This
  can hopefully be done with the help of contrast
  media.

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Thank you