Evaluation of LV systolic function is one of the most common indications for echocardiography, which has important implications in diagnosis, management and follow-up of many cardiovascular disease, especially in heart failure. Contrast agents contain some microbubbles and it can increase backscatter of ultrasound by introducing multiple liquid-gas interfaces23. So they are now widely applied in clinical to assist the detection of endocardial border thus improve the feasibility and stability of quantification in echocardiography.
4.1 LVEF in different conditions
LVEF as the most widely accepted and routinely used parameter, is currently recommended to be measured using biplane modified Simpson’s rule1, which is the delineation of the LV endocardial borders in two planes. Hence, suboptimal image quality would restrict the tracking of endocardial border and result in a modest accuracy and reproducibility of LVEF.
In our study, we used contrast agents in special LVO settings and found it would improve the image quality and the definition of endocardial border effectively. Compared with non-contrast images, both LV volume and LVEF are significantly higher in the presence of contrast agents. This may be attributed to better visualization of endocardial borders with contrast enhancement and avoiding the foreshortening of LV which could make it hard to define the real apex. A multi-center study by R. Hoffmann et al.15 compared both contrast and non-contrast enhanced echocardiography with MRI in the assessment of LV volumes and LVEF. They found that both measurements were underestimated in non-contrast images. With contrast enhancement, the agreement between echocardiography and MRI was significantly increased.
4.2 GLS in different conditions
GLS has been shown to be a more sensitive and robust index to detect LV systolic function than LVEF. And compared with other myocardial deformation parameters like radial and circumferential strains, GLS would be less interfered by potential geometric effect caused by substantial transmural non-uniformity.24 Hence, it is also recommended as a routine measurement in cancer patients undergoing chemotherapy to detect reduction of LV function prior to the decrease of LVEF6. Currently, 2D-STE is widely used to measure GLS, which can track the myocardial speckles without angular dependence. Because GLS is calculated as the average of regional strain, when more than two myocardial segments’ tracking is suboptimal, the calculation should be avoided25. As we mentioned, contrast agents can improve the image quality in echocardiography, so there is a hypothesis that 2D-STE combined with contrast enhancement may benefit the LV function assessment in these patients with more than two suboptimal segments.
In our study, we found it has a better feasibility to calculate GLS in contrast-enhanced echocardiography using VVI analysis. The absolute value of GLS was significantly higher in the presence of contrast agents, and there was a good correlation between GLS measured with and without contrast agents. In LVO images, we control the speed and dose of the injection of contrast agents to make microbubbles homogenously distributed in LV cavity without far field attenuation or apical swirling. And we use the specific LVO settings with low MI of 0.18–0.25 to reduce the interference of microbubbles perfused in myocardium, so we are able to visualize the real endocardium and make it covered by ROI. While in non-contrast images, only subendocardial and subepicardial region of the walls are used for tracking, then GLS is obtained as the average of them. There are several studies demonstrated that myocardial deformation is characterized by a transmural strain gradient.26−29 That is potentially caused by the transmural differences in wall stress, which lead to the endocardium stretching longer in diastole and more shortening in systole. Thus, when the tracking of the real endocardium is included, the absolute value of GLS may be higher.
Medvedofsky et al.16 found that GLS was accurate and reproducible in contrast-enhanced images by using STE software (Epsilon Imaging, Ann Arbor, MI) in patients with poor-quality echocardiographic images. The GLS they measured was just from the analysis of apical four chamber views, however, the anterior wall from apical two chamber views seem to be more vulnerable to poor image quality. Therefore, the assessment of LV systolic function by GLS on the single view may be less accurate. There are also several studies explicated the possibility of speckle-tracking on contrast-enhanced echocardiography with different machine settings and software packages for strain analysis17 − 22. Some of them implied that the presence of contrast agents would decrease the feasibility and stability of the tracking17,19,21,22, so they recommended to perform the analysis after the destruction of microbubbles with high MI. However, the EACVI/ASE inter-vendor comparison study30 suggested that different vendors and software packages may use different algorithms for optimizing image quality and measuring deformation, which could result in the controversial opinions about GLS measurement on contrast images in these studies as well.
In our study, the strain analysis was performed by VVI software13,31,32, which is a novel echocardiographic imaging technique based on speckle tracking. It incorporates speckle, mitral annular motion and endocardial border tracking and assesses innermost myocardial function adjacent to the endocardial border. Thus, with contrast enhancement, it may potentially generate more robust results than those algorithms that can only track the speckles in echocardiography.
4.3 Correlation between LVEF and GLS
In non-contrast echocardiography, the correlation between LVEF and GLS is modest, and it is slightly higher with contrast enhancement. That may imply the fact that both LVEF and GLS could be affected by the detection of endocardial border. Onishi et al.33 found overall linear relationship of GLS and conventional CMR EF, but it appeared to be more curvilinear for subjects with normal EF. Therefore, GLS may have advantage in detection of myocardial dysfunction prior to declination of LVEF, and is recommended in detection of early subclinical cardiomyopathy.
In present study, all patients were divided into two subgroups with EF < 53% in contrast-enhanced images as systolic dysfunction group, and otherwise as normal group. The agreement of both LVEF and GLS measured in different conditions are better in patients with reduced EF. We found it was easier to control the speed of injection in these patients, because with reduced systolic function, it’s less likely to fill LV cavity with high concentration of contrast agents that may cause far field attenuation and interfere the tracking of basal segments. Another possible reason for that is the etiology of these patients, which cause deposition of fibril proteins in the interstitium of myocardium like cardiac amyloidosis34. It’s characterized by thickening of ventricular wall and valves and classic granular sparking in myocardium. Hence, the feature tracking of VVI would be performed more accurately in these patients even without contrast.
4.4 Reproducibility
One month after the first analysis, 10 patients were chosen randomly, and their recordings were reanalyzed by the same operator and another operator respectively. We found that the correlation and agreement were good for both non-contrast and contrast-enhanced images for the same operator. However, the interobserver variability level was higher with or without contrast enhancement. That indicates the routine use of VVI requires adequate training for physicians and sonographers to reduce the variability, and for consecutive study, it would be better to perform VVI analysis by the same operator.
Limitations
One limitation of our study is that we didn’t include patients with cardiovascular diseases specifically, so there is a small number of patients with reduced LVEF. Meanwhile, we didn’t analyze regional strain, thus, we were unable to compare the effect of contrast agents in strain measurements of different segments, or verify the reproducibility of it. However, the purpose of our study is to demonstrate the feasibility of VVI analysis in contrast-enhanced echocardiography and compare the difference of GLS measured with and without contrast enhancement. Global strain can also be computed by averaging the values computed at the segmental level from the same frame, with no more than one segment excluded.35 So the feasibility of GLS may be better than the strain of one single segment and is more accepted in clinical.
The other limitation is that we didn’t assess the LVEF and GLS measurements against CMR as a gold standard. That’s because CMR is expensive and time-consuming, and it’s hard to be applied in all these patients. At the same time, our focus was on the feasibility and comparison of GLS measured before and after contrast enhancement instead of the accuracy which still need a further study.