/  Part I.7 – Echocardiography in Translational Research



Echocardiography in Translational Research

Pierre Monney MD, Xavier Jeanrenaud MD,
Hendrick Tevaearai MD EMBA and Didier Locca MD

A. Introduction

Echocardiography is the the most commonly used imaging test in daily clinical cardiology practice and has been the reference method for cardiac morphological and functional assessment for several decades. Echocardiography is perfomed from a trans-thoracic or trans-oesophageal approach, and is characterized by its low cost, its high availability and its portability allowing to easily perform complete examinations in the laboratory or at the bedside. It allows real time imaging with a high temporal and spatial resolution in a time-efficient manner. From the initial M-modes linear measurements, echocardiography rapidly evolved into 2D imaging, which is now the standard modality of imaging for morphology and function. Doppler echocardiography followed and rapidly became the reference method for valvular assessment; it also provided the possibility of a non-invasive haemodynamic assessment of the patients, including the measurement of the cardiac output, the characterization of the left ventricular diastolic function or the measurement of the pulmonary artery pressure. More recent developments allowed the assessment of the regional myocardial deformation using tissue-Doppler derived techniques or speckle tracking algorithms from standard 2D images, and provided new quantitative measurements of regional myocardial contraction and relaxation. 3D echocardiography was another major recent development, which permitted a more accurate and reproducible assessment of the volume of the cardiac chambers with no limitations related to geometric assumptions or to image orientation. 3D echocardiography greatly improved the morphological assessment of the cardiac valves and it is increasingly used to guide structural interventions in the catheterisation laboratory or the electrophysiology suite.

Despite tremendous technological improvements, some important limitations of human echocardiography are still unresolved. First, the image quality will depend on the position of the heart in the thorax and of the habitus of the patient. The ultrasound beam is completely reflected from bone or lung structures and cardiac images can only be obtain from specific windows –typically parasternal, apical and subcostal, where the heart is in direct contact with the chest wall. Optimal positioning of the patient and –if needed- breathing instructions to the patient allow to obtain the standard images with adequate orientation in the majority of patients. However, in about 5-10% of patients (1,2) image quality remains unsatisfactory with insufficient delineation of the endocardial border or apical foreshortening, preventing a complete quantitative assessment of the cardiac structures. Second, if the left ventricle and left atrium are well characterized with echocardiography, the right cardiac structures are difficult to image because of their position behind the sternum. Imaging of the right ventricle improved with 3D techniques but clear imaging of the right ventricular outflow tract remains difficult for a significant subset of patients. Third, echocardiography is an operator-dependent method and the accuracy and reproducibility of all the measurements performed will depend on the experience of the operator.

These limitations are somewhat counterbalanced by the versatility of echocardiography and by the ease to combine this technique with physical exercise or pharmacological stress, or with invasive or non-invasive simultaneous pressure measurement to derive pressure-volume or pressure-strain loops. The use of LV opacification is safe (3) and can improve endocardial border detection and LV volume quantification, and it can be used to assess myocardial perfusion during rest and pharmacological stress (4).

This chapter will describe the currently available technique for clinical echocardiography in humans, and how they can be applied to translational research in small animal models. Murine echocardiography has specific requirements including the use of a higher frequency linear array probe ( >8 MHz, but up to 70 Mhz) to achieve temporal and spatial resolutions that are adapted to the small size of the animal and to the high heart rate, and a careful sedation of the animal to avoid bradycardia and myocardial depression during image acquisition. Importantly, morphologic images are essentially obtained from the parasternal windows as it is difficult to display non-forshortened views form the apical window, and interpretable images can be expected in >95% of cases with commercially available equipments (5,6).

B. Echocardiographic Measures of Structure and Global Function for Intermediate End-Points

Left ventricular volume, ejection fraction and mass all have important prognostic value and represent important end-points in clinical research (7,8).

Linear measurement is the simplest way to assess left ventricular structure by measuring end-diastolic and end-systolic diameters as well as septal and posterior wall thickness using M-mode (Figure 1), or 2D echocardiography from a parasternal window. M-mode diameters slightly overestimate 2D measurements because of the difficulty to obtain a perfect alignment of the interrogation line to the left ventricle, and M-mode is therefore being progressively abandonned (9). Although the measures are reproducible (10,11), they should not be used to calculate left ventricular volumes because of major inaccuracies related to geometric assumptions (12). Estimation of left ventricular mass is still largely based on calculations from linear measurements (13) but, despite a good reproducibility, the method has a limited accuracy with a systematic underestimation of mass and wide limits of agreement when compared to cardiac magnetic resonance (CMR) (14).

figure 1Figure 1. M-mode acquisition of the left ventricle in parasternal long axis view. The echoes obtained along a single ultrasound beam are displayed in function of time, and myocardial wall thickness and both diastolic and systolic left ventricular diameters can be measured.

Left ventricular volumes and ejection fraction are most commonly calculated from two apical 2D images (Video 1) after manual tracing of the endocardial border (modified biplane Simpson method, Figure 2). These measurements may be inaccurate in case of LV remodelling because they also rely on geometrical assumptions, and their inter-observer reproducibility is only moderate (15,16). When compared to CMR, 2D echocardiography systematically underestimates the LV volumes and to a lesser extent ejection fraction. The use of LV opacification (Video 2) significantly reduces this under-estimation and improves agreement between both methods (17,18). Recommendations for image acquisition and normal values for linar and 2D measurements are described in detail in the current clinical guidelines (19).


Video 1. Two-dimensional standard acquisitions of the left ventricle from an apical window : four-chamber view (upper left panel), two-chamber view (upper right panel) and three-chamber view (bottom left panel)


figure 2Figure 2. Two-dimensional measurement of left ventricular volumes (modified Simpson method). On a 4-chamber view (left-hand images), the endocardial border is traced on the end-diastolic and end-systolic frames. From these tracings, the end-diastolic and end-systolic left ventricular volumes are calculated (summation of discs). To improve accuracy and avoid errors related to an irregular shape of the left ventricle, the same process is repeated on a 2-chamber view (right-hand images) and the measurements averaged to obtain biplane end-diastolic and end-systolic volumes.


Video 2. Apical four chamber view with contrast-enhancement of the left ventricular cavity.


The development of 3D imaging allowed to obtain a volume acquisition of the left ventricle (Video 3) and to directly measure the LV volumes and function without geometrical assumption using a semi-automated algorithm of endocardial border detection (Video 4). This resulted in higher accuracy in the measurement of volumes and ejection fraction using CMR as a reference: comparison between both techniques showed a good agreement with a significantly lower underestimation of volumes with 3D echocardiography as compared with 2D techniques (20,21) and a good intra-observer, inter-observer and inter-study reproducibility (22). The combination of 3D acquisition and LV opacification provided the best agreement with CMR in one study of 50 patients (mean difference of -6 ±14 ml for end-diastolic volume and 0±3% for LVEF) (23). LV mass can be calculated with 3D echocardiography after tracing the endocardial and epicardial border, and this method again showed a very good agreement with CMR and a high inter-observer reproducibility (24). 3D echocardiography is at the present time the echographic method of choice for the assessment of left ventricular structure and function and its high reproducibility is attractive for clincal study, allowing a significant reduction in study sample size as compared with 2D echocardiography. Limitations of 3D echocardiography include the dependence on good image quality, a more limited availability and a low temporal resolution with real-time imaging. To increase image resolution, multi-beat imaging can be performed, but this mandates the collaboration of the patient for breath-holding, and a regular heart rate to avoid stitching artefacts. At last, LV segmentation is performed offline and the post-processing time has to be taken into account in the clinical or research workflow.


Video 3. Three-dimensional acquisition of the left ventricle from a trans-thoracic apical window.



Video 4. Three-dimensional left ventricular volume measurement from the 3D-dataset presented on Video 3. A semi-automated endocardial border detection algorithm tracks the contours of the LV over the cardiac cycle to provide a time-volume curve of the LV, including the maximal (end-diastolic) and minimal (end-systolic) volumes.


Achieving a high temporal resolution is crucial for murine echocardiography as the heart rate is frequently >500/min. A frame rate of 150-200 frames/s will be needed to obtain 15-20 frames per heart cycle and correctly identify systole and diastole. Linear measurements using 2D-guided M-mode represent the current standard due to the very high temporal resolution of this technique ( >1000 frames/s), and they have shown an adequate reproducibility in intra-observer and inter-observer analysis (25). 2D-imaging using a high-frequency probe is technically more demanding but can improve the accuracy of measurement in case of irregular geometry of the ventricle (26) by direct measurement of the LV volume using the monoplane Simpson method or the area-length method from parasternal long axis and short axis views. 3D reconstruction of LV volume from a series of 2D short-axis acquisitions avoids geometric assumptions and showed a high concordance with CMR for LV volumes measurement (27). It is however time-consuming and mandates a good image quality and a regular heart rate. Real-time 3D imaging is not available for small animal models.

C. Echocardiographic Measures of Regional LV Function and Myocardial Deformation

LV myocardium has a a 3-layered structure of obliquely and circumferentially oriented fibers and its deformation during systole is complex in 3 spatial directions (28). LV ejection fraction, as a global marker of systolic function, is limited in describing myocardial deformation at the level of myocardial wall or segment. Newer techniques allowing to measure myocardial deformation (strain) and rate of deformation (strain rate, SR) in longitudinal, circumferential and radial direction, segment by segment, improved our understanding of myocardial function (29). Strain is defined as a change in length of the myocardium from its original length (Lagrangian strain) or as a change in length relative to the length at a previous time instance (natural strain), whereas strain rate is the change of strain over time (30). Strain and strain rate can be measured in longitudinal direction from apical views, and in radial and circumferential direction from parasternal views. Longitudinal and circumferential strains are negative as they describe myocardial shortening, whereas radial strain is positive, corresponding to myocardial thickening in systole. From experimental studies using closed-chest dog and pig models, strain rate has been shown to to be closely related to the regional contractility, while strain better corresponded to regional change in stroke volume (31,32).

Tissue Doppler imaging (TDI) was the first developed echocardiographic technique to assess myocardial deformation. By measuring instantaneous myocardial velocities (Figure 3) at different locations in the myocardium, regional strain rate (Figure 4) can be derived (33). Strain can then be calculated by integrating SR over time (Figure 5). As Doppler-derived technique, myocardial velocities are measured according to the position of the probe and an optimal alignment of the myocardal region of interest to the ultrasound beam is mandatory (34). As a consequence, TDI strain and strain rate can only be measured in longitudinal direction from apical views or in radial direction (anteroseptal and inferolateral segments) from parasternal views. TDI strain and strain rate have been validated against sonomicrometry in an open-chest dog model (35) and against tagged magnetic resonance in humans (36), and normal values in humans have been published (37). TDI strain and strain rate imaging remains technically demanding because of a high susceptibility to noise from movement in the blood pool, to aliasing and to reverberation artefact, resulting in substantial variability even in a normal population (37). An advantage of this technique is its high temporal resolution, allowing for a precise measurement of timing events during myocardial contraction and relaxation.

figure 3Figure 3. From a color tissue-Doppler cine image acquired with a high frame rate (left-hand image), the instantaneous velocities of the myocardium toward or away from the probe can be simultaneously measured during post-processing. Longitudinal velocities of the mitral annular plane are typically characterized by a peak systolic volocity (s’ wave), an early diastolic velocity corresponding to the passive filling of the LV (e’ wave) and a late diastolic velocity corresponding to the active LV filling due to the atrial contraction (a’ wave). The s’-wave is positive as the mitral plane moves toward the transducer in systole, whereas the e’ and a’-waves are negative, corresponding to a movement away from the transducer during diastole.

figure 4Figure 4. From the same color tissue Doppler cine images obtained from an apical window, the the longitudinal strain rate, i.e. the rate of myocardial deformation in the longitudinal direction can be measured. Systolic strain rate (SR-S) is negative as it corresponds to the rate of longitudinal shortening, whereas early diastolic (SR-E) and late diastolic (SR-A) strain rate are positive (lengthening).

figure 5Figure 5. By temporal integration of the strain rate curve (see figure 4), the instantaneous strain can be measured along a myocardial wall. From an apical view, the longitudinal deformation of the myocardium is measured, expressed as the percentage of its original length. The systolic longitudinal strain is typically neagative, as it corresponds to systolic shortening of the LV myocardium.

Speckle tracking technique is a more recent development of 2D echocardiography allowing to measure strain (Video 5, Figure 6) and calculate strain rate (Video 6, Figure 7) from a standard B-mode image. Speckle tracking echocardiography analyses the displacement of individual acoustic markers (speckles) within the myocardial wall during the cardiac cycle and the semi-automated tracking algorithm allows for a frame-by-frame calculation of strain (38). Unlike TDI strain, 2D strain measurement is not performed relative to the adjacent myocardial region, making this technique angle-independent. Furthermore, it allows to assess myocardial deformation in all direction for all myocardial segments (39) (Video 7) as well as myocardial rotation (40). The technique has been validated against sonomicrometry in an open-chest pig model (41) and tagged magnetic resonance imaging in humans (42), and normal values have been published (43). A high correlation has been shown between 2D strain and TDI strain (44) but 2D strain techniques showed a higher reproducibility (45,46). However, high quality 2D images with an adequate frame-rate (50-100 frames per second) is required for an optimal tracking of the acoustic signals (47). Rotation analysis using 2D speckle tracking also has been validated against tagging MRI (48) but its reproducibility is limited by the difficulty to standardize the acquisition of the basal and apical short-axis planes (49). Rotation analysis provides new measurement endpoints like twisting, torsion, untwisting and untwisting rate, that can refine the characterization of myocardial mechanics (50).


Video 5. Two-dimensional longitudinal strain analysis of the left ventricle in apical four-chamber view (upper left panel). The regional strain is provided for each myocardial segment (bottom left panel) as well as the time-strain curve (upper right panel). The strain data over the cardiac cycle can be summarized using a curved color M-mode display (bottom right panel).


figure 6Figure 6. Longitudinal strain by 2D-speckle-tracking echocardiography can be obtained from the 3 standard apical orientations (4-chamber, 3-chamber and 2-chamber views) to cover all the 17 myocardial segments. The regional values of peak systolic strain can be summarized on a bull’s-eye display and a mean peak systolic longitudinal strain value can be calculated for the whole myocardium.


Video 6. From the same apical four-chamber acquisition (video 5), the corresponding two-dimensional strain-rate parameters are obtained.


figure 7Figure 7. By temporal derivation of the data presented on Figure 7, the corresponding regional and global strain rate values are obtained.


Video 7. Two-dimensional circumferential strain assessment from an apical short axis view of the left ventricle. The regional strain is provided for each myocardial segment (bottom left panel) as well as the time-strain curve (upper right panel). The strain data over the cardiac cycle can be summarized using a curved color M-mode display (bottom right panel). From the same image, radial strain and global rotation can be measured (not shown).


Part of the variability in the strain measurement using 2D speckle tracking is related to out-of-plane motion of the myocardium during the cardiac cycle, mainly affecting strain measurement in the basal short axis view, and the recent development of 3D speckle tracking imaging should overcome this important limitation (50,51). 3D speckle tracking (Video 8) has been validated against sonomicrometry in an open-chest sheep model (53) and it has been proposed as a more adequate tool to assess myocardial rotation (54). 3D speckle tracking has been reported to have a better reproducibility for radial strain assessment (55) and normal values have been proposed (56,57). However, a significant variability between vendors and between post-processing softwares has been highlighted (58,59) and more validation is needed before a widespread use of this promising technique.


Video 8. Three-dimensional strain analysis from the 3D dataset of the left ventricle displayed on Video 3. The time-volume curves are displayed for each myocardial segment (right upper panel) and the strain values are summarized as a bull’s eye.


Strain and strain rate analysis provide several new quantitative measures of myocardial function, including peak strain (maximal deformation), systolic strain (maximal deformation occurring before aortic valve closure), post-systolic index (ratio of post-systolic strain to global strain), systolic, early diastolic and late diastolic strain rate, twisting, and untwisting rate (60). Global longitudinal strain has been validated as an index of global left ventricular systolic function (61) with a superior reproducibility as compared with LV ejection fraction (measured by 2D biplan Simpson) (62) and a high prognostic value (63,64,65). In case of ischemic heart disease, strain analysis offers a quantitative assessment of regional function (66). Furthermore, even in case of normal ejection fraction, longitudinal strain analysis is able to detect early systolic dysfunction in the context of hypertension and diabetes (67), heart muscle disease (68,69), inflitrative heart disease (70,71), heart failure with normal ejection fraction (72), valvular heart disease (73,74), of after anti-cancer chemotherapy (75,76).

Strain measurement using TDI or speckle tracking technique has been used in large animal models (35,41,42,77): closed-chest models only allowed to acquire parasternal views for radial or circumferential strain assessment while open-chest models using epicardial echocardiography from the apex were needed for longitudinal strain assessment. Using high-frequency probes achieving frame rates between 225 and 350 frames/s, both TDI and speckle tracking strain could be obtained from parasternal images in mice. While TDI assessment is restricted to radial strain of the posterior wall and circumferential strain of the lateral wall, speckle tracking allows to calculate strain from both short-axis and long-axis parasternal views. Both methods showed a good agreement with invasive measures of systolic function at rest but TDI strain performed better during dobutamine challenge (heart rate >600/min) due to a higher temporal resolution (78,79). TDI strain and speckle tracking strain were able to detect subtle changes in systolic function with more sensitivity than conventional measures of systolic function (80,81).

D. Echocardiographic Measures of LV Systolic Dyssynchrony

Dyssynchrony of the myocardial contraction is an important component in the pathogenesis of systolic heart failure and cardiac resynchronisation therapy (CRT) using bi-ventricular pacing greatly improved the outcome of the patients (82). Due to its high temporal resolution, echocardiography is as an ideal tool to measure the timing of mechanical events during the cardiac cycle and several single-center studies proposed echocardiographic parameters to characterize mechanical ventricular dyssynchrony and predict a favourable response to CRT. Techniques for echocardiographic assessment of myocardial dyssynchrony have been described in detail in the 2008 guidelines of the American Society of Echocardiography (83).

M-mode echocardiography of the LV from a parasternal window has been used to measure the time difference between peak septal displacement and peak posterior wall displacement (septal to posterior wall motion delay) (84). The feasability of this simple parameter is limited in case of ischemic cardiomyopathy when either the septum or the posterior wall is akinetic and its reproducibility was low in a multicentre setting (85).

Global makers of delayed mechanical action of the left ventricle have been proposed, based on pulse-wave Doppler flow measurements across the aortic and the mitral valve. Left ventricular pre-ejection interval (LPEI) is measured as the time interval between the onset of the QRS and the onset of ejection across the aortic valve and is prolonged in case of significant mechanical dysynchrony. Myocardial performance index (MPI) is the ratio of isovolumic times (isovolumic contraction + isovolumic relaxation times) to the duration of systolic ejection and this parameter increases with increasing dyssynchrony (86). Despite being simple parameters, their reproducibility was only moderate in a multicentre trial setting (85), and their ability to predict response to CRT was low.

High expectations were placed into tissue Doppler imaging to assess dyssynchrony. Using this high temporal resolution technique, longitudinal velocities of the basal and midventricular myocardial segments can be assessed with a high precision in all 6 myocardial walls from the apical window. The most frequently used measurement was time-to-peak systolic velocity, the time interval between the onset of the QRS and the maximal myocardial velocity occurring before aortic valve closure. The differences in time-to-peak systolic or maximal velocity between facing walls (Figure 8)(87,88) or the standard deviation of the time to peak systolic velocity measured in 12 different sites (basal and midventricular segments in each of the 6 myocardial walls) (89) have been proposed as criteria to detect LV dyssynchrony and predict response to CRT. Tissue Doppler is however an angle-dependent technique, and the recording of myocardial velocities cannot differentiate between an active muscle contraction and a passive movement of the myocardial wall. These limitations were partly responsible for its low reproducibility in a multi-centre setting (85) and its limited value in predicting the clinical response to CRT.

figure 8Figure 8. Dyssynchrony assessment by comparison of the time to peak longitudinal velocity of two facing ventricular walls. The longitudinal velocity of the basal inferoseptal segment is displayed in yellow and that of the basal anterolateral wall in green. The peak systolic velocity of the basal anteroateral wall occurs 110 ms after the peak systolic velocity of the basal inferoseptal, wall indicating dyssynchrony.

2D speckle-tracking strain analysis is able to differentiate active contraction from passive translational movement and could overcome some limitations of TDI velocity assessment despite its lower temporal resolution. Delay in peak radial strain ( >130 ms) between opposing walls (Video 9) was suggested to be a predictor of EF improvement after CRT (90,91) but these results could not be reproduced in another large study (92). More recently, the calculation of the strain delay index (defined as the sum of the differences between peak global longitudinal strain and peak systolic longitudinal strain in 16 myocardial segments), a marker of the amount of mechanical energy wasted by dyssynchrony (Video 10), has been proposed a promising marker of reverse remodelling of the LV after resynchronization in a multicentre study (93). In this study, the variability of measurement was low, but the feasability of the measurement was only 80%, which may be a practical limitation. Finally 2D strain has also been used to guide the positioning of the LV pacemaker lead by detecting the last activated myocardial segment, and resulted in improvement in outcome after CRT in a randomized controlled (94) study.


Video 9. Two-dimensional radial strain analysis of a mid-papillary parasternal short-axis view of the left ventricle. From the time-strain curves (upper right panel), left ventricular dyssynchrony appears as a shorter time-to-peak radial strain in the anterior and septal segments as compared with the inferior and lateral semgments. The time-to-peak strain values are displayed for each segment (bottom left panel).



Video 10. Two-dimensional longitudinal strain analysis from an apical four-chamber view showing mechanical dyssynchrony. The time-strain curves show and early contraction of the septal segments and a markedly delayed contraction of the lateral wall, that occurs after aortic valve closure.


3D imaging is appealing for the assessment of LV dyssynchrony because it can assess the contraction of all myocardial segments simultaneously. Using the same semi-automated border detection algorithm used for the assessment of EF, postprocessing of the volume data provides individual time-volume curves corresponding to the 16 myocardial segments. The standard deviation of the time to minimal segmental volume expressed as a percentage of the cycle duration (systolic dyssynchrony index, (Video 11) SDI) has been proposed as a quantitative index of LV dyssynchrony (95,96,97). Normal values for SDI have been reported in the normal population (98), but there is no widely accepted cut-off value to predict clinical response to CRT. Apart from the general limitations of 3D imaging including the need for high-quality images, this assessment can be difficult to perform in case of very low systolic function as segmental volume will only minimally change during the cardiac cycle, rendering the definition of the timepoint of minimal segmental volume unprecise (99). 3D SDI has been compared to tissue Doppler velocity techniques and a low agreement was found between both techniques, indicating that significant differences exist when dyssynchrony is assessed using markers of radial or longitudinal mechanics (100,101) and the combination of both techniques could increase the prediction of response to CRT (102).


Video 11. Three-dimensional volume assessment of the left ventricle. The segmental LV volume change over the cardiac cycle is displayed on the bottom right panel. The segmental time-volume curve show marked dyssynchrony. In this example, the SDI (systolic dyssynchrony index, ie the standard deviation of the time-to-minimal segmental volume) was 19%.


The most suitable animal model for LV dyssynchrony is a canine model with left bundle branch block as it is charcterized by an electrical dyssynchrony comparable to human LBBB (103). Dysynchrony assessment in experimental studies was reported using speckle tracking strain in an open-chest dog model (104) and using M-mode from parasternal views in a closed-chest dog model (105). The use of time to peak strain has also been proposed in mice models of ischemia using speckle tracking longitudinal strain measurement from a parasternal long axis image (5).

E. Echocardiographic Assessment of Myocardial Viability in Ischemic Heart Disease

Standard 2D echocardiography has been used as a simple method to assess myocardial viability in ischemic heart disease by simply measuring wall thickness. Transmural fibrous scars are often associated with wall thinning and a wall thickness < 6mm was predictive of absence of function recovery after revascularization (106,107). Despite a high sensitivity, its specificity of this parameter is low, limiting its utility in practice.

Left ventricular opacification using myocardial contrast echocardiography allows to easily assess myocadial perfusion at rest. Myocardial contrast agents are ideally designed for perfusion assessment as they have a pure intravascular distribution. The grading of the myocardial perfusion of each individual segment can be performed semi-quantitatively by visual assessment or quantitatively using using intermittent triggered high mechanical impulse imaging to derive myocardial contrast intensity replenishment curves. The absence of myocardial opacification early after myocardial infarction is highly predictive of an absence of functional recovery (108,109); in chronic ischemic heart disease, preserved myocardial perfusion allows to predict function recovery after revascularization with a sensitivity comparable to that of dobutamine stress echocardiography and 201-thallium scintigraphy (110). The diagnostic performance of contrast echocardiography was reproduced in another study in comparison with 18-FDG-positron emission tomography (111) and its prognostic value demontrated (112).

As ischemic lesions progress from the endocardial muscle layers toward the epicardium, longitudinal myocardial function is expected to be reduced first as the longitudinally oriented myocardial fibers are located sub-endocardially. In comparison with delayed-enhancement CMR, 2D strain and strain rate analysis using speckle tracking technique showed a reduction in longitudinal contraction (Figure 9) in both subendocardial and transmural infarctions wheras a reduction in circumferential contraction was only seen in case of transmural infarctions (113). Early after reperfused acute myocardial infarction, resting global longitudinal strain correlated with the final infarct size and transmural extent (114) and a global strain value < -13.7% predicted functional recovery (115). Although promising and simple, these new techniques need further validation.

figure 9Figure 9. Bull’s eye plot of the 2D longitudinal strain of the left ventricular myocardium obtained in a patient with a lateral myocacardial infarction. Longitudinal strain is severely reduced in the basal to mid anterolateral and inferolateral walls, whereas it appears completely normal in the septal segments. The global longitudinal strain is decreased (-12.7%).

The standard echocardiographic method for viability detection is low-dose dobutamine echocardiography to detect contractile reserve in viable but hibernating myocardial segments. The set-up for this examination is more complicated as it requires the presence of a nurse for drug infusion during the dynamic examination, a continuous cardiac monitoring and the availability of rescuscitation facilities in case of an arrhythmic or ischemic complication of dobutamine infusion. The procedure of dobutamine stress echocardiography is described in details in the dedicated guidelines (2,116). Hypokinetic or akinetic segments at rest, which improve their contraction during low-dose (2.5 to 10 mcg/kg/min) dobutamine have been shown to improve their function after revascularisation. The probability of functional recovery after revascularization is considered maximal when the patient show a biphasic response, with an improvement of contraction with low-dose and a reduction in contraction with high-dose dobutamine, indicating viable but ischemic myocardium (117). The assessment of regional wall motion is classically performed with visual assessment and, as a consquence, high image quality is required. Despite improvements in global image quality, the inter-institution reproducibility of this technique is still not optimal (118). Even with these limitations, this technique has been largely validated in clinical practice (119) although the prognostic value of viability assessment has been recently challenged (120). The use of LV opacification can be used to improve endocardial border detection and confidence in visual interpretation (121). The use of deformation imaging using tissue Doppler or speckle-tracking strain and strain rate in combination with dobutamine stress echocardiography allow to obtain a quantitative assessment of changes in segmental contraction. In a pig model, the assessment of TDI-derived myocardial strain and strain rate during dobutamine stress was able to detect myocardial infarction and differentiate between subendocardial and transmural necrosis (122). In a clinical setting, an increase in longitudinal strain rate >0.23 s-1 by tissue Doppler was proposed as a cut-off value to predict viability using 18-FDG PET as a reference (123). However, in comparison with standard visual assessment, the use of deformation imaging during DSE only slightly improves the accuracy for viability detection, and tissue Doppler techniques appear more accurate than speckle tracking in this context (124,125).

In a murine model of infarction, resting TDI radial strain rate was superior to wall thickening to identify transmural myocardial infarction (126), and to differentiate between transmural and non-transmural infarction in the acute and chronic phase (127). Resting LV opacification using intravenous contrast accurately detects area at risk or myocardial infarction following coronary artery ligation (128).

F. Echocardiographic Detection of Myocardial Ischemia

Dobutamine stress (or exercise) echocardiography is the standard method for ischemia detection using echocardiography. Detailed procedure of the test is described in the dedicated guidelines (2,116). Briefly the segmental contraction of the myocardium is assessed at rest, during low-dose (5-10 mcg/kg/min) dobutamine, peak-dose dobutamine (40 mcg/kg/min ± atropine to reach 85% of the maximal predicted heart rate) and during recovery. An ischemic myocardial segment presents normal contraction and becomes hypokinetic during stress, or presents the typical biphasic response described in the previous section. As described for the viability assessment, ischemia detection using DSE is usually performed with visual assessment only. The use of LV opacification improves wall segment visualization (121) (Plana) and the use of deformation imaging could provides a quantitative assessment of segmental myocardial contraction at rest and during peak stress. Animal studies using tissue-Doppler (129,130), described a reduction of longitudinal systolic strain and an increase in post-systolic strain during acute ischemia. This pattern has been confirmed in patients during DSE where a reduction in systolic strain and the presence of a post-systolic index (the ratio of post-sytolic to maximal peak strain) >20% were predictive of ischemia (131,132). Reduction of systolic strain rate was also found to be predictive of ischemia (133). Similarly, speckle-tracking longitudinal strain reduction with DSE was associated with ischemia in an animal model (41) and in patients (134) altough the quality of tracking may be reduced at high heart rate during peak stress (135). Diagnostic accuracy and prognostic value of DSE have been largely validated in clinical studies (136,137).

Myocardial contrast echocardiography is performed for ischemia detection by assessing myocardial perfusion, and uses a purely intravascular contrast medium. The principle is the comparison of myocardial opacification at rest and during maximal coronary hyperemia induced by adenosine or dipyridamole. Intermittent triggered high mechanical impulse imaging is used for myocardial perfusion assessment during contrast infusion and consists in delivering a brief high mechanical flash of ultrasound to destroy the micro-bubbles of and observe the replenishment of the myocardium. Qualitatively, normal perfusion is characterized by a complete opacification of the myocardium within 5 heart beats at rest and within 2 heart beats at peak stress. Quantitative assessement of the replenishment curves allows to measure myocardial blood volume and blood velocity (β) and to calculate myocardial blood flow (138,139). The ratio of myocardial blood flow (or blood velocity as a surrogate) during stress and at rest allows in turn to calculate coronary flow reserve (140). This method has been validated against SPECT (141) scintigraphy and in a head to head comparison of the two methods, MCE showed a superior sensitivity but a lower specificity (142). However, the method of image acquisition and the post-processing of the data are technically demanding and associated with a significant learning curve.

A last method of ischemia detection with echocardiography is the direct measurement of flow in the epicardial coronary arteries using pulse wave Doppler at rest and during adenosine or dipyridamole coronary hyperaemia (143,144). Image acquisition is technically more challenging (145) but in experienced hands and with the use of myocardial contrast, the mid to distal left anterior descending artery can be visualized in almost 100% of cases. The distal circumflex and right coronary arteries are more difficult to assess but the success rate was 92% and 88% for the RCA and LCx respectively in a recent study (146). The Doppler spectum of coronary flow at rest shows a predominantly diastolic flow and the flow increases with coronary hyperaemia during adenosine infusion. Since adenosine is not associated with a significant dilation of the epicardial coronary arteries, the ratio of the coronary mean velocity flow at peak hyperemia and at rest allows to estimate coronary flow reserve (CFR) of the dependent myocardial territory with good reproducibility (147,148). This method has been validated against invasive coronary flow measurement, SPECT (149) and PET (150).

In murine models, coronary flow Doppler of the left coronary artery at rest and during adenosine vasodilation was used to calculate coronary flow reserve. CFR was significantly reduced in case of coronary artery stenosis and in case of pressure overload hypertrophy (151,152). A quantitative assessment of myocardial blood flow using LV contrast opacification at rest and during pharmacological vasodilation was reported to be feasible in 98% of mice and showed a close correlation with a reference myocardial blood flow measurement using microspheres (153).

G. Echocardiographic Assessment of Right Ventricular Volume and Function

A precise assessment of right ventricular size and function is of great importance as these parameters provide independent prognostic informations in right-sided (154) and left-sided heart diseases (155,156).

The right ventricle is more difficult to assess with echocardiography due to its retro-sternal position. Its complex structure with a crescentic basal shape and a separated outflow tract does not allow a complete visualisation of its morphology in one single 2D imaging plane. RV size is classically assessed separately from an apical “RV-focused” 4-chamber view (with no visualization of the RV outflow tract, (Video 12)) and a parasteral view (to visualize the RVOT and the pulmonary arteries), which will provide complimentary informations. Several standard linear or area measurements to assess RV size from these views have been recommended in the recent guidelines and normal ranges have been defined (157). However, the ideal apical imaging plane for RV is difficult to standardize and the proposed normal values are not adjusted to age or body size, limiting the accuracy of these methods.


Video 12. Two dimensional modified four-chamber view to assess the right ventricular morphology. On this view, the right ventricular outflow tract cannot be assessed due to the complex shape of the RV. From this view, the measurement of the RV diastolic and systolic area allows to calculate the fractional area change, a standard parameter of RV systolic function.


RV function can be estimated with the fractional area change (FAC), a surrogate of RVEF calculated from the RV area in diastole and in systole from a RV-focused apical 4-chamber view. FAC correlates with the RVEF measured with cardiac MRI (158) but overestimations of RV function are expected to occur if the RVOT is dilated or hypokinetic. Other commonly used indices of RV function are based on the longitudinal displacement of the tricupsid annulus using M-mode (tricuspid annulus plane systolic excursion, TAPSE) or its systolic velocity using tissue Doppler (Figure 10). Altough TAPSE showed a prognostic value in pulmonary hypertension (159), it is angle-dependent and it estimates the whole RV function from the motion of one single wall, limiting its reliability is case of regional dysfunction (160). Deformation imaging of the RV free wall using tissue Doppler or speckle tracking have been used to characterize RV function. Despite their feasability, the normal values derived from different studies were inconsistent and these methods are not recommended for clinical use until further validation (157). RV strain studies allowed however to better understand the the complexity of the RV contraction and its tight dependency on loading conditions (161).

figure 10Figure 10.Conventional markers of right ventricular systolic function include linear measurements of longitudinal contraction of the RV free wall. Top panel : TAPSE (tricuspid annular plane systolic excursion) is the distance between the diastolic and systolic position of the tricuspid annulus measured with M-mode.

Bottom panel : The maximal systolic velocity of the tricuspid annulus longitudinal motion (s’) is measured on a pulse-wave tissue-Doppler tracing of the basal RV free wall.

3D echocardiography recently offered a tool to globally assess the RV morphology without any geometrical assumptions (Video 13). With this technique, RV diastolic and systolic volumes can be obtained to calculate a true RV ejection fraction using dedicated post-processing softwares (Video 14). As for 2D imaging, the retro-sternal postion of the RV may be seen as a limitation and significant image drop-outs can be observed in the RVOT region. Despite this limitations, 3D volume measurement is feasible in 81-94% of patients and correlates well with CMR (162,163,164). Normal values adjusted to age and gender have recenly been made available (165).


Video 13. Three-dimensional acquisition of the right ventricle.



Video 14. From the 3D acquisition of the RV presented on Video 13, a frame by frame measurement of the right ventricular volume can be performed using a dedicated semi-automated endocardial border detection software. Minimal and maximal RV volumes, as well as a time-volume curve of the RV can be obtained. (EDV – end-diastolic volume ; ESV – end-systolic volume ; SV – stroke volume ; EF – ejection fraction).


Right ventricle cannot be clearly visualized from trans-thoracic echocardiography in mice due to interference of the sternum. Transoesophageal echocardiography using an intravascular ultrasound probe has been proposed to overcome this limitation despite the lower frame rate of the probe (166).

H. Non-Invasive Hemodynamic Assessment

Basic haemodynamic assessment can be performed by combining simple linear and pulse wave Doppler measurements. Trans-aortic stroke volume is calculated from the measurements of the LVOT diameter (to calculate LVOT cross-sectional area) and the pulse wave Doppler of LVOT flow. This technique is limited by a significant variability as it relies on several measurements from different orientations. Stroke volume can also be measured at mitral or pulmonary level using the same technique, and the comparison of the stroke volumes at different locations can be used to quantify valvular regurgitant volumes or intra-cardiac shunts. Technique for standard Doppler measurements is presented in detail in the dedicated clinical guidelines (167).

Diastolic function and LV filling pressures estimation is an important but difficult challenge of Doppler echocardiography. While echocardiography can accurately measure pressure gradient, its ability to accurately assess filling pressures is controversial (168). The mitral inflow pattern using pulse-wave Doppler (E and A waves, (Figure 11)) was the first described parameter to assess diastolic function. Although easy to acquire (169) and predictive of outcome (170) it is highly load-dependent and cannot be used as a single parameter. Tissue-Doppler measurement of mitral annular early diastolic velocities (E’) is a less load-dependent parameter of LV relaxation (Figure 12) correlated with invasive measures of LV relaxation (171) and provide strong prognostic informations (172). The combination of both parameters, the E/E’ ratio, provides a robust semi-quantitative estimate of LV filling pressures (173), which has been validated against invasive pressure measurement in stable (174) and decompensated patients (175). In case of inconclusive results, the multi-parametric approach of diastolic function assessment has to be completed with additional parameters including pulse wave Doppler recording of pulmonary venous flow (176), mitral flow during Valsalva manœuvre, timing measurements of E and E’ waves (177,178), systolic pulmonary artery pressure estimation and left atrial volume measurement. Guidelines for diastolic function assessment describe in detail these parameters and how to interpret them in combination to grade diastolic dysfunction and estimate LV filling pressures (179). Deformation imaging is a new but promising tool for assessment of LV relaxation. Using speckle-tracking echocardiography, longitudinal strain rate during isovolumic relaxation has shown to correlate with invasive parameters of LV relaxation and the ratio E/(SRIVR) has been suggested to more accurately predict LV filling pressures compared to E/E’ ratio (180). Finally, LV torsion is increased with early diastolic dysfunction (181) and LV untwisting rate is correlated with invasive parameters of LV relaxation. However, as untwisting rate also depends on LV systolic function (182), more data are needed before rotation parameters can be recommended to assess diastolic function.

figure 11Figure 11. The profile of the diastolic transmitral flow is an important parameter of diastolic function assessment. It consists in a pulse-wave Doppler spectrum acquired at the tip of the mitral leaflets from an apical window, and is characterized by a early peak (E-wave) corresponding to the early passive filling and a late peak (A-wave) corresponding to the late active filling related to the left atrial contaction. The ration of the E to A velocity, the E-wave deceleration time and the duration of the A-wave are important parameters to characterize diastolic function.

figure 12Figure 12. The profile of the mitral annular plane motion assessed by pulse-wave tissue Doppler is also important to characterize diastolic function. From an apical window, the Doppler sample is successively placed at the basal septal and basal lateral wall and the spectrum obtained is characterized by a peak of systolic motion (s’) toward the transducer and two diastolic peaks of diastolic motion (e’ and a’) correspondig to the early and late filling phases of the left ventricle. The ratio of the E wave of the mitral inflow (see Figure 11) and the e’ wave of the mitral annulus motion is correlated with with the left ventricular filling pressures.

Left atrial (LA) size is part of the hemodynamic assessment as LA enlargement is a marker of chronically elevated LV filling pressures (183). It is also a powerful prognostic marker of adverse cardiac events including atrial fibrillation, heart failure, stroke and death (184). LA volume (Figure 13) is a better prognostic marker than LA area or diameter and is the recommended parameter to acquire (185). 3D echocardiography allows to measure LA volume without geometric assumptions (Video 15) and is more accurate than 2D measurements; it showed an excellent agreement with CMR and a good reproducibility (186). By measuring the LA volume at different time instances (minimal, maximal and pre-A volume), different markers of LA function can be calculated for LA reservoir, conduit and contractile function (187). 2D speckle tracking echocardiography recently offered new quantitative parameters of LA deformation by measuring atrial longitudinal strain (Video 16) and strain rate (188). Reduced longitudinal LA strain during systole can be seen as an early marker of reduced LA compliance and is associated with diastolic dysfunction and reduced exercise capacity (189). In combination with the mitral E/E’ ratio, atrial strain during systole allow to estimate LA stiffness, suggested as an accurate marker to identify diastolic heart failure (190).

figure 13Figure 13. Left atrial maximal volume measurement using the biplane Simpson method. The endocardial border of the left atrium is traced on a 4 chamber and 2 chamber view (end-systolic frame) to calculate the left atrial volume. The left atrial appendage and the pulmonary veins are typically excluded from the left atrial volume.


Video 15. Three-dimensional measurement of the left atrial volume, providing a time-volume curve of the left atrium over the cardiac cycle.



Video 16. Two-dimensional longitudinal strain of the left atrium from an apical four-chamber view. With the start of the cardiac cycle defined as the ECG p-wave, the time-strain curve (upper right panel) show an initial negative value corresponding the the atrial wall shortening during active atrial contraction. Thereafter, left atrial strain is negative corresponding to left atrial wall lengthening during ventricular systole, with a maximal value at end-systole.


Pulmonary artery pressure (PAP) is a major prognostic marker (191) and an important diagnostic parameter for diastolic dysfunction as most cases of elevated PAP are secondary to elevated LV filling pressure. Systolic PAP is measured from the maximal velocity of the tricuspid regurgitation jet, corresponding to the pressure gradient between right ventricle and right atrium during systole (192). Careful alignment to the jet orientation is mandatory to avoid underestimations and no RVOT outflow obstruction should be present. Right atrial pressure, estimated from inferior vena cava diameter and its collapse during inspiration, is added to the RV-RA gradient to obtain sPAP (193). This calculation showed linear correlation with invasive sPAP although the strength of the correlation was moderate, resulting in an imperfect diagnostic accuracy (194). Other parameters have been proposed for the estimation of mean PAP, including tricuspid regurgitant jet time velocity integral (195), pulmonary flow acceleration time (196) and early-diastolic velocity of the pulmonary regurgitant jet (197), and can be used as additional markers of pulmonary hypertension. Pulmonary vascular resistance PVR) can be assessed as the ratio of tricuspid regurgitant flow maximal velocity and pulmonary forward flow time-velocity integral (198). A good correlation was reported for moderately elevated PVR, but this index becomes inaccurate when PVR increases to >8 Wood units (199). Further indexes of pulmonary haemodynamics have been summarized in a recent review (200).

Pulse-wave and color Doppler can be used in murine echocardiography from parasteranal and apical 4 chamber views to measure trans-mitral, trans-aortic or trans-pulmonary flow velocity. Diastolic function in mice can be characterized using transmitral flow pattern (E and A waves, isovolumic relaxation time) (201), but mitral annular velocities measured with tissue Doppler imaging (E’ and A’ waves) are more sensitive makers of early diastolic dysfunction (202,203). As in human, the E/E’ ratio is correlated with LV end-diastolic pressures in mice (204).

I. Echocardiographic Measures of Cardiac Valves Morphology and Function

The high temporal resolution imaging combined with Doppler techniques for flow measurement make echocardiography an ideal technique for the assessment of valve morphology and quantification of valvular stenosis or regurgitation. Two-dimensional echocardiographic assessment of valve disease is clinically validated and represents a key examination in the management of valvular heart disease (205), but some important limitations are too keep in mind. Metrics to characterize valve stenosis include trans-valvular gradient measurement, direct valve planimetry, or calculation of aortic orifice area using continuity equation (206). The accuracy of these techniques depends on an optimal alignment of the probe with the structure of interest, which is not achievable in all patients. Furthermore, continuity equation is a calculation based on three different parameters and potential measurement errors at several levels can increase the variability. 2D color Doppler is used to quantify valvular regurgitations by measuring the vena contracta width of the regurgitant jet or by calculating the effective regurgitant orifice area (EROA) using the proximal isovelocity surface area (PISA) method. Regurgitant volumes can in turn be calculated by multiplying EROA by the time velocity integral of the regurgitant jet but this calculation will also rely on multiple measurements, increasing its variability. More importantly, vena contracta width and PISA methods assume that the regurgitant orifice is circular and the valve insufficiency can be underestimated in case of an oval or irregular orifice, as it is typically seen in functional mitral regurgitation (207).

3D echocardiography provides a more comprehensive assessment of valve morphology and can overcome some limitations of 2D imaging by avoiding geometric assumptions. Morphologic assessment of the mitral valve dramatically improved with 3D echocardiography (most commonly performed from a trans-oesophageal route) as it provided a direct en face visualisation of the leaflets allowing an accurate description of localized prolapses (Video 17). Post-processing of the volume datasets using commercially available quantification softwares provides several metrics of the valve morphology including size and shape of the mitral annulus, coaptation area, leaflet area, tenting volumes or billowing height (Figure 14)(208). These parameters can help to better characterize the mechanism of regurgitation and estimate the chances of a successful surgical repair. In case of mitral stenosis, the 3D approach garantees that the planimetry of the valve orifice will be measured in the right imaging plan, independently from the alignment of the probe, resulting in a better accuracy than 2D techniques and a high reproducibility (209). In mitral regurgitation, color Doppler 3D echocardiography is used to directly measure the cross-sectional area of vena contracta of the jet without geometric assumptions. This technique has been validated against CMR and showed a high reproducibility and a better accuracy than 2D methods (210,211), but it still needs further clinical validation. Other 3D methods for quantification of mitral regurgitation are based on 3D stroke volumes measurement and on the 3D PISA method, but their validation is less well established than for vena contracta area (21). Finally 3D echocardiography is an important tool to plan and to monitor several percutaneous valve interventions including transcatheter aortic valve implantations, balloon mitral valvuloplasty, mitral clipping, or paravalvular leak plugging (213).

figure 14Figure 14. Mitral valve quantification model of the valve shown on video 17, obtained after manual tracing of the mitral annulus and the mitral leaflets at end-systole on the original 3D dataset (left-hand panel : surgical en-face view ; mid panel : lateral view from the anterior commissure ; right-hand panel : superior view from the aorta).


Video 17. Three-dimensional acquisition of the mitral valve with trans-oesophageal echocardiography. The image is oriented to match the normal orientation during cardiac surgery (surgical view, with the aortic valve superior to the mitral valve). On this image, a marked end-systolic prolapse of both anterior and posterior leaflets is seen.



Echocardiography is the first-line imaging modality for morphologic and functional assessment of the heart in clinical cardiology. The technique has been largely validated and new modalities including myocardial deformation imaging, 3D echocardiography and myocardial contrast echocardiography provide new promising quantitative endpoints for translational and clinical research. However, a high-level training in image acquisition and post-processing is to emphasize to reduce the variability in measurement as echocardiography is an operator-dependent technique. Despite that and some other well-known limitations including poor image quality in a subset of patients or angle-dependency of Doppler measurements, echocardiography remains an attractive research modality because of its high temporal and spatial resolution, its versatility, and the rapidity of image acquisition. Echocardiography could be successfully used in human and animal research, with almost all modalities (except real-time 3D due to its insufficient temporal resolution) being applicable to even small animal models, highlighting its central role for translational research in cardiology. Finally, the portability, the wide availabilty and lower cost of the technique could represent further important advantages in the research setting.

Table 1. LV Structure and Global Function

table 1

Table 2. Regional LV function and myocardial deformation

table 2

Table 3. Dyssynchrony assessment of LV contraction

table 3

Table 4. Assessment of myocardial viability

table 4

Table 5. Assessment of myocardial ischemia

table 5

Table 6. Assessment of right ventricular volumes and function

table 6

Table 7. Non-invasive hemodynamic assessment

table 7

Table 8. Cardiac valves morphology and function

table 8


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