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Myocardial Perfusion Using Contrast Echocardiography. Fiction or Reality?

Ricardo E Ronderos, MD, PhD

Hospital San Juan de Dios and Instituto de Cardiologia La Plata,
Universidad Nacional de La Plata, La Plata, Argentina

   Myocardial perfusion depends on coronary artery blood flow, using conductance vessels as epicardial coronary trunks, resistance vessels as coronary perforants, arterioles and capillaries. Blood volume is distributed all through myocardial wall, but is mostly present at subendocardial area, filled by approximately 80% of myocardial blood volume.

   Myocardial flow studies were performed longly in research scenarios in the last 2 decades, almost always using radioactive microspheres, as intravascular tracers. Those animals' studies allowed an extensive knowledge of coronary flow dynamics, but in controlled conditions and research situations.

   It was not possible to use any intravascular tracer in clinical scenarios to understand pathologic findings during ischemic events. Moreover, data about coronary blood flow were extrapolated from those animals' experiences, to human physiology, with absence of strong evidences that those concepts could be wrong in the clinical field.

   Recently after a long period of research, new generations of industrially and hand made designs of ultrasound contrast agents appear.

   Gas containing microbubbles, stables enough to achieve persistence injected in human circulation, and sized to cross human capillaries, was developed with different formulas. Some of them, have a similar rheology as blood red cells, when mixed by intravenous injection, with human blood pool.

   Ultrasound contrast agents were designed to create gas liquid interfaces to increase the reflectivity of ultrasound. But, contrast microbubbles are strongly reactive to ultrasound energy, with intense response to positive and negative pressures when insonificated.

   During the period of positive pressure, bubbles are compressed reducing their size, and on the other hand, at time of negative pressure bubbles dilate by rarefaction increasing radius more than they change during time of compression. (Figure 1)

Figure 1


   Using frequencies as those, which are useful in clinical diagnosis, those bubbles resonate producing non-linear responses, allowing echo machines to detect harmonic frequencies, (Figure 2) as well as to destroy microbubbles using ultrasound insonification by manipulation of levels of energy.

Figure 2

   Those properties are a powerful tool to manage bubbles dynamic and persistence in blood pool, fact that associated with well-known microbubbles rheology, becomes the key to manipulate an intravascular tracer to understand aspects about red blood cells dynamics, in a clinical scenario.

   Ultrasound technology, developed so fast in the last years, produced 2 trends of software programs based on 2 different concepts: 1- To use of high levels of ultrasound energy to destroy ultrasound contrast agents' microbubbles, inducing high level of harmonics response and simultaneously cleaning up the myocardial capillary field in the area where ultrasound beam insonificates myocardial microcirculation (Figure 3) and 2- To use very low energy levels, as low as possible to avoid bubbles destruction, but producing microbubbles resonance, inducing low levels of harmonic responses from tissue, but with enough bubbles resonation to be detected by a high sensitive Doppler mode as Power Doppler harmonics.

Figure 3

   Different manufacturers developed different approaches; all of them designed to minimize wall motion artifacts and tissue harmonic production, using a type of real time background subtraction and not any destruction of circulating microbubbles. (Power pulse inversion, Power modulation, etc.) (Figure 4 - 5)

Figure 4

Figure 5

   Both techniques demonstrate amazing results during last 3 years, allowing depicting important issues about myocardial blood flow, which became the background to interpretive clinical results in different applications.

   Most data were published about myocardial flow dynamics using ultrasound contrast agents, and also different protocols were developed in clinical research, both at rest and during stress, to prove usefulness of myocardial perfusion studies by contrast echocardiography.

   There were few papers, conducted by well-known investigators, showing very bad results in comparison with coronary angiography and nuclear perfusion studies. Those protocols were performed regardless knowledge and training of the laboratories participating in terms of contrast agents applications, and also using old and new software to look at myocardial perfusion. Those defects in protocol design were probably the explanation of poor results obtained, and also the pessimistic atmosphere generated around contrast echocardiography in the field of myocardial perfusion study.

   Contrast agents improvement was faster than technology improvement. This reality acts against a coordinated grow up of the clinical applications of these state of the art echo techniques.

   On the other hand, there are not yet any intravascular tracers, to be applicated in clinical field. Then it is not possible to use a GOLD STANDARD for comparison in clinical trials.

   It is well known there are deep differences between anatomic diagnosis (coronary disease diagnosticated by coronary angiography) and functional studies (exercise or pharmacologic stress) using nuclear medicine or conventional stress echocardiography, nevertheless correlation between those methods are significant.

   Diagnosis of perfusion defects using the clinical gold standard, Thallium or sesta MIBI exercise or vasodilators stress SPECT, are worldwide accepted as the primary clinical tool, for decision making in patients with coronary artery disease.

   Although radioisotopes used for clinical diagnosis are known to have not an intravascular dynamic and beside they depends on cellular integrity and metabolic function for caption, they were selected as a gold standard for myocardial perfusion clinical studies. Most publications about these topics also compared with quantitative coronary angiography, an all of them showed a high degree of correlation for diagnosis of induced or rest perfusion defects and coronary obstruction.

   Few different types of stress, including exercise, inotropics and vasodilators were included in clinical protocols.
Destructive technique, triggered intermittent harmonic studies, has demonstrated an enormous impact in clinical diagnosis of perfusion defects adding a great value over the information from wall motion analysis. This is a key topic because additional information using perfusion data increases sensitivity in coronary artery disease diagnosis, without loss of specificity that highly improves test accuracy. (Figure 6 - 7)

Figure 6

Figure 7

   What is the limitation for a wide application of echocardiography to study myocardial perfusion?

1- It is mandatory to understand physical basis about microbubbles physics and dynamics
2- Education should be planned to train technicians and physicians in new software and contrast agents' manipulation and characteristics
3- Echocardiography should be performed by well training groups of physicians or by technicians with close collaboration of medical staff
4- Multicenter protocols performed by worldwide echo laboratories, well trained in contrast studies and with tight study protocols should be performed after consensus meetings
5- The protocols approved by consensus have to be applied on different pathologies and should be check in controlled follow up studies to demonstrate the impact of use of this technique in health care and health economy
6- Contrast agents and Ultrasound Manufacturers should meet efforts to go ahead, contributing in education and financial aspects of about described issues
7- FDA or local countries similar institution regulations should be quickly accepted, using research potential all around the world specially in countries where physicians are directly involved in echo studies performance.

   All those topics above are not so far in the horizon to be afraid about the future and present of these techniques. Focus group meeting showed not difficulties to share experience and coordinated efforts to achieve those issues. Financial aspects seem to be the big deal at the present time.

   It is important to keep in mind that nevertheless other images techniques are growing up quickly, in the field of myocardial perfusion; echocardiography is a world wide accepted diagnostic tool with real time images and presence anywhere in hospitals and medical offices with relatively low costs.

   Acute coronary syndromes, stress echocardiography using adenosine or dipyridamole vasodilator stress, as well as dobutamine studies are ready to go in clinical practice if are used by well-trained medical groups.

   Exercise stress echocardiography is going to be ready quickly with the improvement of software to increase frame rate in non-destructive technique studies.

   Value of myocardial blood volume and flow quantification will be prove in the near future with the standardization of protocols, opening a big new window for knowledge about ischemic cardiomyopathy and coronary artery disease.

   Moreover to recognize non reflow phenomenon easily bedside in real time becomes a tool for viability studies, and triggered destructive techniques has already prove value of refilling of capillaries in long trigger intervals to recognize easily viable myocardium.

   It is correct that it is necessary to achieve a big pool data in long term follow up to create the evidence about utility of all these information in the clinical practice. But the only way to achieve this goal is to apply slowly and seriously those state of the art echocardiography powerful techniques in the clinical scenario.

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
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Dr. Armando Pacher
Technical Committee - CETIFAC
President
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