Early Diagnosis Of Myocardial Ischemia By Strain-Rate Imaging, Real-Time Three-Dimensional Echocardiography, And Myocardial Contrast Echocardiography During Adenosine Stress

BackgroundCoronary artery disease is a main killer to human health. Early diagnosis and effective treatment is of great importance to improve the patients' prognosis. However, it is still an urgent problem about how to make an early diagnosis accurately and non-invasively, although many invasive, non-invasive techniques are already used on the diagnosis of coronary disease.Improved ultrasound contrast agents and better understanding of interaction between the microbubbles and ultrasound has resulted in "contrast-specific" imaging modes —myocardial contrast echocardiography (MCE). Combined with the emergence of contrast-specific imaging modalities and new contrast agents, along with quantitative analytical method, intravenous MCE is now a feasible and promising noninvasive technique for perfusion assessment. Technological advances have recently enabled the imaging of myocardial contrast in real time using low-power emission which is named as real time MCE. It can detect nonlinear responses from microbubbles without destroying them, so coupled with short, high-energy impulses (fast low-angle shot, FLASH) that completely destroy the microbubbles within the field of view, this new method offers the unique opportunity to assess microbubble replenishment kinetics in real time, and fulfill the ultimate aims of simultaneouslyassesssing myocardial perfusion and wall motion function in real time. Furthermore, this kind of newly developed MCE has a good spatial resolution, particularly in the axial direction. Therefore, it provides a technological basis for the quantification of the MBF.Ischemic heart disease typically produces regional abnormalities of contraction. Hyperkinesis of normal areas may compensate for impaired function of an abnormal region, leaving global LVEF normal or only minimally depressed. Thus, compared with the analysis of global ventricular function, the assessment of regional wall motion is more sensitive in detecting ventricular dysfunction in such patients with both therapeutic and prognostic implications. Normal wall motion consists of simultaneously myocardial thickening and inward motion of the endocardium toward the center of the chamber. Using current echocardiographic techniques, the evaluation of segmental myocardial contractility is usually based on the visual interpretation of endocardial excursion and myocardial contraction. This visual interpretation makes it very subjective and strongly dependent on the experience of the reader, making more objective and noninvasive methods desirableStrain imaging (SI) and strain rate imaging (SRI) are new techniques for assessing regional myocardial function, which overcomes some of the limitations of conventional tissue Doppler imaging (TDI). This represents a more logical method of assessing regional contractile function as these datasets are not influenced by the function of adjacent myocardial segments and are less dependent upon the direction of shortening in relation to the transducer. Strain rate is a measure of the velocity of deformation of myocardium, and integration of this parameter with respect to time gives myocardial strain, a measure of the percent compression of myocardium during systole. This approach is independent of the translational motion of the heart and is also seldom affected by the Doppler angel of incidence. Thus strain and strain rate imaging help to discriminate reliably active motion from passive motion and provide technological basis for accurately quantifying left ventricular segmental contraction. Furthermore, the technique can document short-lived subtle changes in deformation patterns, such as post-systolic shortening.Stress echocardiography is an adjunctive tool to assess myocardial perfusion and left ventricular function. It can detect the patients' coronary reserve function, record wall motion and kinetics in real-time during stress, provide evidence about the position, scope and severity of the ischemic myocardium and the basis for therapeutic stratification as well as prognostic evaluation. Pharmacological stress tests include dobutamine, adenosine and dipyridamole stress, among them adenosine stress echocardiography (ASE) has been studied widely in abroad. Traditionally stress echocardiography is usually based on two-dimensional echocardiography. The diagnostic and prognostic value of two-dimensional stress echocardiography have been established in numerous published studies. However, two-dimensional echocardiography technique has important practical limitations in its application during stress. Multiple 2D views of the left ventricle must be obtained from more than one window to completely visualize all segments. These time-consuming and operator-dependent 2D acquisitions are particularly problematic during peak stress when the time available for imaging is very brief. If the acquisitions are not completed within a critical period of time, important diagnostic information may be lost, resulting in inaccurate interpretations.The introduction of real-time three-dimensional echocardiography (RT-3D) imaging impressed us through its ability to rapidly acquire images with visualization of the entire LV in any number of different planes simply by rotation and slicing the acquired three-dimensional data set. Furthermore, a high level of operator skill is not required to obtain diagnostic quality RT-3D images at peak stress. Once a volumetric data set is acquired by RT-3D, matching views for baseline and peak stress can be aligned for a precise comparison of the same segments. Previous research already proved RT-3D can accurately assess left ventricular wall motion.There are already numerous studies about the assessment of myocardial contrast echocardiography for myocardial blood reserve, myocardial blood flow, myocardial transmural gradient and its diagnostic value combined with vasodilators. However, whether adenosine stress combined with strain rate imaging as well asthree-dimensional echocardiography can be used to detect ischemic myocardium andregional myocardial function is unknown.Objective1. To observe the influence of strain-rate imaging (SRI) combined with adenosine stress echocardiography on regional myocardial function of ischemic myocardium and investigate the diagnostic value of this approach for myocardial ischemia.2. To test the accuracy of using real-time three-dimensional echocardiography (RT-3D) to detect global and regional function of left ventricle during adenosine-induced stress.3. To investigate the feasibility of real-time contrast echocardiography (MCE) in assessing myocardial ischemia during adenosine stress testing.Methods1. Establishing animal modelsEleven dogs of either sex and average body weight 17kg were anesthetized withsodium pentobarbital (30mg/kg IV) and ventilated. An intravenous line for drug infusion was established and the electrocardiographs were continuously monitored. A lateral thoracotomy was performed, and the heart was suspended in a pericardial cradle. An occluder was placed around the proximal left anterior descending coronary artery (LAD) and an ultrasonic transit-time flow probe (2.0 to 2.5mm) was placed proximal to the occluder and connected to a flowmeter. Then moderate ischemia (defined as LAD resting flow was decreased by 60%~70%) and complete occlusion of coronary artery were produced by constricting LAD.2. Experimental protocol(1) For each animal, heart rate, flowmeter measurements, and tissue Doppler imaging (TDI), RT-3D images, MCE are acquired at baseline. Subsequently, adenosine is infused at 140ug.kg"'. min'1 for 6 minutes, and measurements were repeated.(2) Fifteen minutes after adenosine parameters had returned to baseline, moderate LAD stenosis were imposed by constricting the occluder to decrease LAD flow by 60%~70%, and recordings were repeated. Then adenosine was administered again and measurements were repeated.(3) Finally, LAD was completely occluded for 90 minutes, and recordings were repeated before and after adenosine administration in this state. At the end of the experiment, KCI (30 to 50 ml) was injected into the left atrium. The left ventricle was cut into 1-cm-thick slices along short-axis and soaked in 1.5% 2, 3, 5 triphenyltetrazolium chloride (TTC) for 10 to 15 minutes.3. Echocardiographic Image Acquisition(1) Tissue Doppler image acquisitionAnimals were scanned from an apical window with PHILIPS IE33 ultrasound scanner (Holland) with 2-4 MHZ array transducer. At baseline, during ischemia and infarction, 5 heart cycles of the apical 4-, 2-chamber and longitudinal views were captured in color tissue Doppler mode. The image sector was set as narrow as possible, which resulted in a color tissue Doppler frame rate between 186 and 228 frames per second. Echo data were stored digitally for subsequent analysis.(2) 3D data acquisitionFull volume -three dimensional echocardiography images were acquired using PHILIPS IE33 ultrasound scanner by a matrix array transducer X3.1. Record the images before and after adenosine administration at baseline, during ischemia and infarction respectively.(3) MCE image acquisitionTwo-dimensional gray-scale echocardiography and real time MCE imaging were performed in the apical four-chamber, two-chamber and longitudinal views by Sonos 7500 ultrasound scanner. SonoVue was intravenously infused at a rate of 1.5ml-min"' and about 2 minutes after infusion of the contrast agent when myocardial contrast opacification appeared to reach a steady state, the "flash" key was triggered to emit 8-10 frames of transient high MI (1.5) for microbubble destruction followed by immediate, automatic return to low MI (0.1) imaging for recording microbubble replenishment. At least 15 cardiac cycles of every destruction-replenishment sequence (at least 10 after flash) are obtained. Record the images before and after adenosine administration at baseline, during ischemia and infarction. MCE data are stored on magnetic optical disk as raw data and transferred digitally.4. Data processing and Measurements(1) Strain and strain rate data processingWe used PHILIPS IE33 ultrasound scanner (Holland) online QLAB analysis software to analyze the images. A 16-segment model of left ventricle recommended by the American Society of Echocardiography was used. Choosing each segment as a region of interest (ROI), the strain and strain rate curves were displayed automatically by the system. We measured peak systolic strain rate (SRpeak sys), the maximal systolic strain ( e max), strain during ejection time ( e et) , and postsystolic strain (e ps). The values of strain rate and strain are expressed in seconds' and percent respectively and are negative in shortening1 and positive in lengthening myocardium. The ratio of e ps/ e max and e ps/ e e( were calculated to account for systolic shortening and overall curve amplitude.(2) 3D data measurementsWe used PHILIPS IE33 ultrasound scanner (Holland) online QLAB analysis software to analyze the images. First, we pressed the 3DQ Advanced key, then marked the mitral valve annulus and apex in end-diastole and end-systole and manually traced left ventricular endocardial line. Finally the system automatically gave the curves of global and regional volume and ejection fraction of 17 segments (including apex).(3) MCE data analysisWe performed the quantitative assessments using the QLAB analysis software. Measurements of signal intensity (dB) were done by manually placing regions of interest (ROIs) in 16 segments respectively. The myocardial signal intensity (SI) was plotted against time and then fitted to an exponential function: Y(t)=A(l-e"IM)+C, where Y is SI at any time during the replenishment, A is the plateau SI reflecting microvascular cross-sectional area or myocardial blood volume (MBV), P is the rate of SI rise reflecting the mean microbubble velocity corresponding to myocardial flow velocity, and C is the intercept at the origin. The product of A and 3 provides a measure of MBF. Result:1. strain and strain rate parameters:In non-LAD segments: There were no changes of strain and strain rate during ischemia and infarction compared with baseline, nor after adenosine was administered (P>0.05) .In LAD segments: 1. During ischemia peak systolic strain rate (SR peaksys) decreased significantly compared with baseline (-1.89 s"1 ±0.7 s"1 vs -1.43 s"1 ±0.7 s"1, P<0.05). Maximal systolic strain (￡ max) and strain during ejection time ( e el) reduced slightly, while postsystolic strain ( ￡ ps ) increased minimally but had no significance( P>0.05). The ratio of ￡psto ￡ ct ( ￡ ps/ ￡ et) significantly increased (0.57 ± 1.1 vs 3.07±3.0, P<0.05) . 2. During infarction both e et(0.79%±4.0%) and ￡ max (0.90%±5.7%) are positive, SR peaksys(-0.54 s'1 ±0.6 s'1) is almost zero. LAD segments showed significant increase in ￡ ps, ￡ ps/ ￡ max and ￡ ps/ e et (P E max, and SR peak sys clearly reduced( PO.01), ￡ ps/ ￡ max and e ps/ ￡ ? significantly increased compared with ischemia ( PO.01). 3. Changes with adenosine: At baseline and during infarction the values of strain and strain rate did not change after adenosine was administered. During ischemia SR peak sys (-1.43 $"'±0.7 s'1 vs -0.85 s"1 ±0.7 s'\ PO.05) andeet (-3.99%±4.8% vs-1.16%±5.1%, P<0.05) significantly reduced in LAD segments after adenosine was administered (PO.05), while e ps (-3.79%± 3.0% vs-7.03% ±3.4%, PO.05) , ￡ ps It et and ￡ ps/ ￡ max clearly increased (PO.05, P0.05) while significantly decreased during infarction (62%±18% vs 39%±7%, PO.01). RESV increased significantly during infarction (0.43ml + 0.34ml vs 0.63ml ± 0.32ml, pO.Ol). Compared with ischemia, REF value decreased significantly (61%±21% vs 39%± 7% , PO.Ol) while RESV increased clearly(0.29ml±0.17ml vs 0.63ml±0.32ml, P<0.0\) during infarction.The standard deviation of peak systolic time in 16 segments were compared between each state. Compared with baseline, it didn't change significantly during ischemia, whereas significantly increased after adenosine was administered (38ms± 27ms vs 52ms±llms, PO.01). Compared with baseline and ischemia, it increased significantly during infarction (38ms±27ms vs 85ms±7ms, PO.05) (26ms±8ms vs 85ms ± 7ms, P<0.01) but did not change when adenosine was administered. 3.MCE parameters:At baseline peak signal intensity (A),maximal rise of signal intensity (P) and A ? 3 increased significantly under adenosine stress in both LAD and non-LAD segments (P0.05);When adenosine was administered, the value of A decreased slightly and P and A ? P increased minimally but had no significance. During infarction A, P and A ? P decreased markedly compared with baseline and ischemia ( P<0.05), but there was no changes before and after adenosine (P>0.05) .Conclusion1. Combined with adenosine stress echocardiography, SRI can quantitativelydifferentiate ischemic myocardium from nonischemic myocardium. The ratio of postsystolic strain ( e ps) to maximal systolic strain ( E ps/ e max) and to strain during ejection time( e ps/￡ ?) can be used as an objective index to differentiate ischemic myocardium.2. Real-time three-dimensional adenosine stress echocardiography is feasible and sensitive in the detection of ischemic myocardium and is capable of measuring global and regional volume and systolic function of left ventricle.3. The addition of low-mechanical-index MCE to standard imaging during adenosine stress testing improves detection of myocardial ischemia.