Myocardial Contrast and Stress Echocardiography: New Frontiers

Myocardial contrast echocardiography (MCE) is a well-defi ned technique to improve delineation of the endocardic borders. It has been increasingly used for the assessment of myocardial perfusion, due to the development of techniques which proportionate simultaneous analysis of myocardial perfusion and function in real-time, it also increases the sensitivity of stress testing for the detection of CAD and it distinguishes between stunned and infarcted myocardium after acute ischemia.


Introduction
The assessment of myocardial perfusion by echocardiography following intravenous injection of ultrasound contrast agents has proved to be feasible [1]. Low-mechanical index imaging techniques that cause minimal microbubble destruction let simultaneous analysis of myocardial perfusion and function in real-time [2]. Real-time myocardial contrast echocardiography (RTMCE) increases the sensitivity of Dobutamine stress testing for the detection of CAD [3] and can distinguish between stunned and infarcted myocardium after acute ischemia [4].
The Dobutamine-Atropine Stress Echo (DASE) is a wellestablished method to noninvasive evaluation of the patients with known or suspected CAD. The ischemic myocardium evaluation is based on the detection of reduction of the systolic myocardium thickness by two-dimensional echocardiography. Those changes are induced by the balance between offer and consumption of oxygen during stress by Dobutamine. Metaanalysis studies have demonstrated that both DASE and myocardial contrast perfusion stress echocardiography are a clinical tool for the detection of CAD [5].
The importance of Dobutamine stress echocardiography (DSE) is well gathered in the risk stratifi cation after acute myocardial infarct and also to evaluate myocardial viability in patients with ischemic cardiomiopathy. The contractile reserve detection can be utilized to predict myocardial regional function recovery in patients with chronic CAD. The method above is more specifi c to evaluate functional recovery after procedures of surgical revascularization than the methods which analyze the presence of viability by the metabolic integrity of myocardial cell, as scintigraphy by 201  stress echocardiography a method with high practicality and reproducibility to CAD evaluation in many situations [6,7]. New Frontiers. Peertechz J Biomed Eng 3(1): 001-010.

Pharmacological considerations and physiological basis to detection of ischemia by dobutamine-atropine stress echocardiography
Among the pharmacological agents used to induce stress, Dobutamine is the most utilized in the clinical practice to evaluate ischemia and myocardial viability. Dobutamine is a catecholamine with half-life between two and three minutes, that present good tolerance and, because its positive inotropism and chronotropic effect, may cause increment in the oxygen consumption by the myocardium [8].
Although cardiovascular stress testing does not defi ne the degree of coronary stenosis, it determines the physiological importance of a particular blood fl ow obstruction. Reduction in the coronary fl ow cause myocardial ischemia because the imbalance between the consumption and supply of oxygen [9].
The myocardial ischemia occurring in areas addressed by an artery with signifi cant narrowing degree obey a sequence of events known as ischemic cascade. The reduction or absence of myocardial thickening systolic expressed by segmental motility alterations are an early phenomenon sensitive and specifi c to ischemia [10]. The global and regional left ventricular function evaluation by echocardiography during stress allows not only the diagnosis, but also the determination of severity and extent of myocardial ischemia. Moreover, the echocardiography is able to identify, by analysis of the various myocardial segments, coronary artery ischemic area-related and new resources as Speckle tracking echocardiography (STE) that is a method of quantitative assessment of myocardial function complementary to ejection fraction (EF) and visual evaluation. Standard STE analysis, demands manual tracing of the myocardium whereas automated function imaging (AFI) offers more convenient (based on selection of three points) assessment of longitudinal strain. Both methods provided good and similar feasibility with only 1% segments excluded from analysis at peak stage of DSE with shorter time and lower coeffi cient of variance offered by AFI. Global and regional longitudinal strain achieved by faster and less operator-dependent AFI method correlate well with standard more time-consuming STE analysis during baseline and peak stage of DSE [11].

Evolution of the echocardiography protocols under stress by dobutamine-atropine
The conventional Protocol consists of intravenous infusion of D obutamine started in dose of 5 mg/kg/min and increased to 10, 20, 30 and 40 μg/Kg/min in three stages minutes [12].
Diagnostic endpoints of the test are: positive echocardiogram (new onset wall motion abnormalities or worsening of baseline dissinergy); achievement of 85% of maximal predicted heart rate (220 -age); severe chest pain and/or diagnostic ST-segment changes. The test is stopped without diagnostic endpoints for: Intolerable symptoms; hypertension; hypotension; supraventricular arrhythmias (supraventricular tachycardia or atrial fi brillation); or ventricular arrhythmias (ventricular tachycardia; frequent, polymorphous, premature ventricular beats) [13].
Over the years, some modifi cations have been made in DSE protocols. An early atropine administration during the DSE has been proposed to reduce the test duration [14]. Tsutsui et al. [15], evaluated the safety, effi cacy and diagnostic accuracy of the early injection of atropine in a larger number of patients (n = 1664), compared with the conventional protocol (n = 3163).
The early atropine protocol proposed consisted in beginning atropine injection in the dose of 20 μg/Kg/min of Dobutamine.
The incidence of serious adverse effect was similar in both protocols (0.3% versus 0.4%; p = NS). The sensitivity, specifi city and accuracy of the early atropine injection to CAD detection was 83%, 89%, and 86%, respectively, and conventional protocol were 85%, 77% and 82% (p = NS between the groups).
The authors concluded that early atropine injection is a safe and effective alternative to conventional protocol, keeping similar diagnostic accuracy to CAD detection. The early atropine administration safety during DASE also was confi rmed in a population of elderly patients (≥ 70 years old) [16].
Another modifi cation in the conventional Dobutamineatropine protocol proposed by Mathias et al. [17], is metoprolol injection in bolus at stress peak, to increase diagnostic accuracy of the exam. This modifi cation consists in the injection of 5 mg of metoprolol in a 1 minute at the stress peak. When the heart rate is below 100 beats per minute or at most within 3 minutes after an injection of metoprolol the post-metolol images are acquired.  [18], defi ning 16 myocardial segments. However, a new segmentation including 17 segments were proposed, due to the advent of contrast echocardiography and the need for standardization of segmentation not only by echocardiography, but also for other methods of image, such as myocardium scintigraphy and positron emission tomography [19]. For semi quantitative assessment of segmental motility, scores are given to each of the left ventricle segments, based on evaluation of the endocardium thickening and in the degree of wall contraction, being the value 1 given to normal segments, value 2 to hypokinetic, value 3 to akinetic and value 4 to dyskinetics, in all stages of the test. The score index of segmental motility is obtained by the sum of the scores given to every one of left ventricle segments divided by the number of segments analyzed.

Technical aspects and interpretation of the images
The test must be interpreted as positive whenever the presence of ischemia appears, in the form of new alteration during stress in the left ventricle segmental motility, which are expressed by augment in the score of more than one segment of the LV at least a point. When changes already exists in segmental motility at rest the test, it is considered positive if there are deterioration of motility compared to the pre-existing, or when changes of the left ventricle presenting at rest improves with low doses drug and later worsens with high doses, indicating viability and myocardial ischemia, respectively. Viability assessment is made by demonstrating improvement in the myocardium motility with low doses of Dobutamine, and this response can occur at higher doses, especially in patients using beta-blockers.

Diagnostic value and prognosis of dobutamine-atropine stress echocardiography
When compared the physical stress testing with DASE, the later has increased sensitivity and shown greater specifi city for the diagnosis of CAD.
Many studies in literature have compared the diagnostic accuracy of different types of stress echocardiography [20,21].
While the DSE and by physical stress presents similar diagnostic accuracy, the dipyridamole stress echocardiography seems to present a somewhat diagnostic smaller, and this difference can be attributed a lower sensitivity of dipyridamole in the identifi cation of uni arterial disease (38% to dipyridamole, 70% for physical test and 61% to Dobutamine).
The addition of atropine to DSE increases the diagnostic accuracy and reduces the percentage of ineffective tests, especially in patients using beta-blockers [22]. These fi ndings were also supported by Pingitore et al., in international multicenter studies EPIC (Echo Presenting International Cooperative Study) [23] and EDIC (Echo Dobutamine International Cooperative Study) [24]. Mathias et al. [25], showed that DASE is a secure and accurate method to diagnostic CAD in patients with or without previous alterations of ventricular motility.
Tsutui et al. [26] showed that although a new protocol of  One the strategies proposed by Mathias et al. [17], to improve DASE sensitivity was the rapid injection of metoprolol in the stress peak with acquisition of post-metoprolol images in maximum range of three minutes. After metoprolol injection, occurred improvement in both sensitivity and accuracy.
Multiple factors can lead to a decrease in the defi nition of the endocardium borders mainly in the stress peak. An important technological advanced introduced was tissue harmonic image (THI) [29], that brings signifi cant benefi ts of reproducibility and exequibility of the stress echocardiography [30]. Harmonic imaging, in which a pulse is transmitted at one frequency and received at twice the transmitted frequency, was originally developed to detect the nonlinear vibrations of ultrasound contrast microbubbles. Early in contrast imaging, however, researchers noticed that the images acquired prior to the arrival of the contrast had better image quality than those made at the fundamental, even at the higher frequency.
It had long been know that sound propagating through tissue created harmonics of its center frequency. Tissue is generally considered to be incompressible and the speed of sound independent of pressure. However, at high acoustic amplitudes, sound speed is slightly higher than at ambient pressure and the peak of the sound wave actually travels faster than the local sound speed. Conversely, in the trough, the speed of sound is slower. This leads to peaking of the sound wave, and the creation of harmonics [31]. The other aspect of THI that has an even more dramatic effect on image quality is its ability to reduce artefacts from shallow structures. Acquisition of ultrasound images are often between ribs, or through surface fat layers. Ribs and fat layers produce distortions, refl ections and reverberations that can lead to a near-fi eld haze often seen in fundamental imaging. THI reduces this problem because the imaging beam is not created at the skin surface but by the propagating wave, and therefore does not even exist in the fi rst couple of centimetres [32]. Another important contribution to improve the quality of images during stress echocardiography was the use of contrast agents based in microbubbles.

Diagnostic value and prognosis of dipyridamole stress echocardiography
The addition of myocardial perfusion (MP) imaging during dipyridamole real time contrast echocardiography (DipRCE) improves the sensitivity to detect coronary artery disease, but its prognostic value to predict hard cardiac events in large numbers of patients with known or suspected CAD remains unknown.

Physical stress echocardiography
Physical stress echocardiography (PSE) has high sensitivity and specifi city, and is more accurate than ECG, Treadmil Test and resting echocardiography in the detection of CAD [34]. LV WMA detected by PSE occur earlier than angina or ST-segment abnormalities [34]. Additionally, PSE also has an additional value in the location and quantifi cation of myocardial ischemia as well as in the prediction of adverse events in patients with established CAD [34]. PSE presents high sensitivity and specifi city to detect myocardial ischemia [35] both in patients without a history of prior intervention and in those previously submitted to percutaneous coronary intervention or coronary artery bypass graft surgery [35]. Detection of ischemia with exercise electrocardiographic testing is limited in patients with left bundle bunch block. PSE also face some limitations in these patients because of the paradoxical motion of the interventricular septum [36]. The prognostic accuracy of myocardial perfusion and stress echocardiography appeared similar. PSE provides signifi cant information for predicting outcome in patients with LVSD and known/suspected coronary artery disease [37]. PSE proved to be a safe modality of stress, with non-fatal complications only. Advanced age and enlargement of the left atrium are predictive of cardiac arrhythmias [38].
Another advantage of PSE is the radiation-free nature.

Role of the stress echocardiography in risk stratifi cation after acute myocardial Infarct
The echocardiography at rest and during stress provides a variety of information's about the left ventricular function, myocardial viability and presence of ischemia, with important therapeutic implications and prognostic after myocardial acute infarct. The GISSI study [39] showed that left ventricle function is one of the main predictors of cardiac mortality after myocardial acute infarction, with larger increments mortality associated with the progressive reduction of ventricular ejection fraction. News parameters refl ecting left ventricular (LV) function as strain and strain rate provide strong prognostic information in patients after AMI. These parameters were superior to EF and WM in the risk stratifi cation for long-term outcome [40].
There are landmarks studies in literature demonstrating the effectiveness of prognostic stratifi cation with stress echocardiography by dipyridamole and Dobutamine in different subsets of patients after acute myocardial infarct as the EPIC and EDIC study [41].

Echocardiography evaluation of myocardial viability
The contractile improvement that occurs during stress refl ects the functional cellular contractile mechanism. A simple echocardiographic analysis at rest provides information about the myocardial viability. Pierard, et al. [42]. Showed

New advances in DASE and contrast echocardiography
The tissue Doppler is better for quantifi cation of the myocardium fl ow at rest and during stress, with most studies suggesting an increase in sensitivity in detecting ischemia when compared to visual analysis [45]. However, its routine use in Echocardiographic Laboratories is still limited, and studies involving more number of patients are still required to consolidate the technique.
The contrast echocardiography is gaining space. The contrast agents are solutions that contains gas microbubbles with the blood cells size, whose interface with the liquid ambient is highly refractional, improving the echocardiographic signal where they are [46]. In patients with multivessel disease and balanced ischemia, the addition of contrast with myocardial perfusion assessment, is not only able to overcome the limitation of false negative rate on a per-patient basis, but may also depict multivessel myocardial perfusion defects more effi ciently than others techniques, thanks to high spatial resolution. Myocardial perfusion assessment during MCE, although not always technically feasible, has a very high spatial and temporal resolution which can easily demonstrate multivessel sub endocardial perfusion defects during maximal vasodilation [49]. Porter et al [2]. Showed that the analysis of myocardial perfusion in real-time associated with DSE improved the sensitivity to CAD detection. In this study, the overall concordance between the analysis of myocardial perfusion and quantitative angiography was of 83% (k = 0.65), meanwhile the concordance between the analysis of segmental motility and quantitative angiography was of 72% (p = 0.07). Some studies suggests that STE is associated with changes in LV volume or function regardless of underlying mechanisms and deformation direction. Meta-regression demonstrates a strong association between peak longitudinal systolic strain and adverse remodeling [52].

Echocardiographic strain and strain rate imaging
Echocardiographic strain and strain rate imaging is a technology enabling more reliable and comprehensive assessment of myocardial function. The spectrum of potential clinical applications is very wide due to its ability to differentiate between active and passive movement of myocardial segments, to quantify intraventricular dyssynchrony and to evaluate components of myocardial function, such as longitudinal myocardial shortening, that are not visually assessable. The high sensitivity of both Tissue Doppler Imaging (TDI) and two-dimensional speckle tracking derived strain and strain rate data for the early detection of myocardial dysfunction

Tissue doppler-derived strain and strain-rate Imaging
TDI is accepted as a sensitive and suffi ciently accurate echocardiographic tool for quantitative assessment of cardiac function [54,55]. Several tissue Doppler velocity parameters appeared to be useful for the diagnosis and prediction of long-term prognosis in major cardiac diseases [56,57]. Taking into account all the aspects mentioned above it is not surprising that TDI-derived strain and strain rate (SR) measurements are not highly reproducible (more than 10-15% interobserver variability). However, in the hands of very experienced and highly trained operators this method can be a valuable non-invasive tool for routine clinical use to evaluate the myocardial contractile function. Despite all limitations this technique has been initially validated with sonomicrometry and also with magnetic resonance imaging [59,60].

Non-doppler speckle-tracking derived 2d-strain imaging
Non-Doppler two dimensional (2D)-strain imaging derived from speckle tracking is an echocardiographic technique for obtaining strain and SR measurements [60,61]  Using higher frame rates could reduce the under-sampling problem, but this will result in a reduction of spatial resolution and consequently less than optimal region of interest (ROI) tracking [62], Low frame rate increases the spatial resolution, but because speckle-tracking software uses a frame-by-frame approach to follow the myocardial movement and searches each consecutive frame for a speckle pattern closely resembling and in close proximity to the reference frame, with too low a frame rate the speckle pattern could be outside the search area, again resulting in poor tracking [63].
It is also important to know that different tracking algorithms potentially produce different results and therefore it should be kept in mind that a periodical update of the software package conceivably infl uences reference values.
Although speckle-tracking derived 2D-strain and TDIderived strain calculations do not give the same values (2D-strain imaging gives lower SR values), strain and SR measurements obtained by these two different imaging techniques correlate well [61]. For the LV, the reproducibility of 2D-strain measurements is better than that of TDI-derived strain measurements. The intraobserver and inter observer variability for 2D-strain and SR measurements were found to be low: 3.6% to 5.3% and 7% to 11.8%, respectively [61] Ingul et al., found lower interobserver variability for non-Doppler 2D-strain measurements in comparison to TDI-derived strain measurements and automated non-Doppler 2D-strain measurements also appeared signifi cantly less time consuming [64]. The lack of angle dependency is a great advantage of non-Doppler 2D-strain imaging in comparison to TDI-derived strain data.

Real time 3-dimensional dobutamine stress echocardiography
Two dimensional contrast-enhanced DSE is used clinically to diagnose stress-induced wall-motion abnormality (WMA).
Aggeli et al. [66], in a study with 56 patients referred for coronary angiography, were examined by 2DE and RT-3DE during the same Dobutamine stress protocol showed that RT-3DE identifi es wallmotion abnormalities more readily in the apical region than 2DE, which may explain the tendency towards higher sensitivity in the left anterior descending artery territory. RT-3DE results were validated using angiography as reference and fi ndings indicate diagnostic equivalence to 2DE, with the advantage of considerable shorter acquisition times .

Conclusions
Due to the level of sensitivity, specifi city, positive predictive value, negative predictive value and accuracy, stress echocardiography perhaps has the highest overall utility and is the most preferred and prescribed modality for the assessment of CAD. Pharmacologic stress echocardiography and MCE turn out to be the most cost-effective and risk-effective window. Finally, echocardiography will be seen in the future not only as a diagnostic tool in those affected by cardiovascular disease but also as a method for prediction of risk and perhaps activation of targeted treatment.