Myocardial contrast echocardiography in routine clinical practice

1. Myocardial contrast echocardiography in routine clinical practice

2. WHY ?

3. Clinical and economic outcomes assessment with MCE, Leslee et al, Heart 1999.

4. 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 weak—several thousand times weaker than myocardium—and so lies below the displayed dynamic range”

5. 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.

6. Physics in ultrasound • Unlike solid tissue, gas bubbles have acoustic properties that vary with the strength of the insonating signal. When insonated ----> gas bubbles pulsate-----> 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.

7. It is a remarkable coincidence that gas bubbles of a size required to cross the pulmonary capillary vascular bed (1–5 mm) resonate in a frequency range of 1.5–7 MHz, precisely that used in diagnostic ultrasound.

8. 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. (<100 kPa) (100 kPa–1 Mpa)

9. 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.

10. 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 (> 1.2) is used to achieve bubble destruction in power Doppler imaging, and • ultra low MI (< 0.1) required to induce linear oscillation of microbubbles required for real time myocardial perfusion imaging.

12. 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

13. 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.

15. 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.

16. 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.

17. 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 agents—for example, Optison, SonoVue), greatly increasing the duration of the contrast effect. • Third generation agents—not yet commercially available—will use polymer shell and low solubility gas and should producemuch more reproducible acoustic properties.

18. 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 destruction—a 20 G or greater cannula should be used. • Very small volumes of contrast are needed using second generation agents (< 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.

21. 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 3–10 bubbles, • a medium shunt 10–20, and • a large shunt > 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.

24. 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

25. 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.

26. 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 5–10% 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.

27. 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

31. LVO PROTOCOLS FOR A BOLUS INJECTION OFCONTRAST

34. 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.

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. ‘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.

41. 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 2·4 ± 1·6 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.

42. 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

43. 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).

44. 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 >70%) 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.

45. In a study conducted by Meza et al. MCE had a good negative predictive value (>80%) 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 = 0·61, 80% agreement, >50% 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 = 0·001). • 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.

46. 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.

47. 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.

48. 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.

50. 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.