Is deformation imaging by ultrasound useful?

by Asbjørn Støylen, dr. med.

Contact address: asbjorn.stoylen@ntnu.no




The previous paragraph on "how to" and clinical evicence in the main section has been moved to a separate section in order to avoid too slow uploading as the website grows. It deals with the approach to using deformation imaging by ultrasound in a practical way, as well as referring some of the the accumulating clinical evidence for the utility of the methods.
This section updated: June 2011.
The page is part of the website on Strain rate imaging.






Other sections:

Measurements of strain and strain rate by ultrasound

Basic principles of ultrasound and scanner technology.

Mathematics of strain and strain rate

Back to main website index

So far, deformation imaging have had difficulties in becoming completely airborne in clinical practice, opinions may vary:


Gentoo penguin
 Wandering albatross has difficulties in taking off from water.
Storm petrel in full flight.
Take your pick.




The number of publications are enormous, but the use in daily clinic is still limited. The limitations being both the experience dependency, initially poor user friendliness, and variability of results. The limitations of the methods may scare potential users as well.  The new speckle tracking applications may be more user friendly (seductively so, one might say), but the actual use in the clinic is still limited, and the methodological limitations severe.

Global functional measurements by longitudinal annulus displacement and velocity, as well as global strain, have all been shown to be better discriminators and prognosticators than other measurements of global function (FS and EF), maybe with the exception of Wall Motion Score Index (189), however, the WMSI being more or less useless in cardiomyopathies as discussed above.

It is also no doubt that the methods have lead to a deeper understanding of both physiology and geometry of myocardial mechanics, as the present website attempts to show. However, the clinical utility relies on documentation in clinical studies.

In clinical evidence, the main point is whether they give added diagnostic value, compared to basic echocardiography. This has been less well documented. From a puristic point of view, only clear documentation of added clincal value to B-mode based WMS is evidence for the utility of deformastion imaging. This will be reviewed more in detail below.

However, in clinical echocardiography, an echocardiographic examination always consists of using all the available, more or less circumstantial evidence, weighing findings against each other and arriving at a conclusion. This will usually be fairly certain in the hands of an experienced clinician, even if single measurements are not. This is a fundamental property of all echocardiography. Thus, clinical ultrasound will partly be a craft, not pure science. And this includes using all of the methods one is familiar with.

This is also the case with deformation imaging, and this should be the basic approach, deformation imaging being part of the total evidence, and can serve as an aid to diagnosis, as shown in the next section on how to interpret findings. This means that this will be a help, and part of the total evidence in selected cases, not the obvious ones. But used this way, the added value, used with discrimination, is  difficult to document scientifically in studies. I think that scientific evidence showing that the method works, may be sufficient reason to use the method if one is familiar with it. This means that if the diagnostic value is given for a method, it can be used as part of the total information, and in this way being useful in an integrated approach.This means than even without documentation for added information value, one might always find something for use in the total echocardiographic assessment.


Arctic fox hunting under Auk mountain.
It may be possible to sniff out some information extra by deformation imaging. 


Of course, this also means discarding parts of the information that are not up to image quality standard, and also that are incionsistent with the total picture. This is discussed below.


Below are a couple of examples of selected cases where B-mode diagnosis is difficult, while deformation imaging helps. Further examples are found in the text, where deformation imaging may be of use in both timing and extent of pathology.



Small apical infarct. This may be difficult to see, and Echo at admittance was initially considered normal. The same case is shown in more detail above.
 Tissue Doppler based strain rate and strain showing hypokinesia in the apex (yellow and red curves), peak systolic strain of - 5% and -8%, strain rate of - 0.35 and -0.8 s-1 both segments with post systolic shortening, as contrasted with normal deformation in the base (green and cyan).


Inferior infarct. Hypokinesia of the basal segment. Not immediately evident. The same infarct is shown above.
 Strain and strain rate. Basal hypokinesia and post systolic shortening (yellow curves). Also normal curves in the inferior apex as well as in the anterior wall (red and cyan).
In both these examples, the 2D strain was less clear.

Normal values for strain and strain rate per gender and age are provided here. It may be assumed that there is little difference between levels (apical, midwall and basal) or between walls. With the limitations inherent in basic ultrasound and in the specific methods, the careful weighing of the evidence in terms of the methods limitations is thus an integral part of the examination, and a knowledge of the methods themselves is essential.  Below, I have tried to give some guidelines in using the methods, in order to achieve robust results.

Quantitation may also make it easier to follow the function in a regional dysfunction as in an infarct, as shown below.


Inferior infarct at day 1, showing akinesia in the basal segment (yellow curve) and hyperkinesia in the apex (blue curve). The hyperkiesia can be explained by the load reduction due to the lack of force from the infarcted segment. (Image courtesy of Charlotte Björk Ingul). The same patient at day 7. Function in the basal segment (yellow curve) can be seen to be nearly normalised, and the shortening of the apical segment (blue curve) is correspondingly reduced.  (Image courtesy of Charlotte Björk Ingul).

In one study (188), there was an improvement of WMS in the infarcted segement from 2.7 to 2.2 (Decimals due to the averaging), While peak systolic strain rate improved from -0.24 s-1 to -1.2 s-1 in the segments with severely reduced function, and from -0.6 s-1 to -1.1 s-1 in the segments with moderately reduced function, showing strain rate to be a help in assessing recovery of function compared to WMSI.

How to interpret strain and strain rate data in terms of regional systolic function


Normal limits versus cut off values

When using numerical values the fundamental understanding that there may be a difference between the cut off values between normal and abnormal, established in studies, and the normal limits in a general healthy population as illustrated below.
Normal range of a variable, defined as mean ± 2SD. Difference between a normal and patient population. The two populations each have a separate distribution, but  the two distributions are widely separated, and the cut off point corresponds to the upper normal limit. In this case, there will be no difference between what is normal by any definition. In this case, the two populations have a higher degree of overlap. The optimal cut off point is the one that defines the best separation, i.e. the point that gives the highest AUC. However, this point can be seen to be far below the upper normal limit of the healthy population.

This means that in examining undifferentiated patient, the normal limtis should be considered. It is also important that the longitudinal function is age, and to lesser degree gendes dependent, and thus gener and age specific values should be considered.

In a recent population study, the north Tröndelag population (HUNT) study, 1266 subjects without known heart disease, hypertension and diabetes were randomly selected from the total study population of 49 827, and subjects with clinically significant findings on echocardiography (a total of only 30) were excluded. (153) This is the largest strain rate echocardiographic population study ever. End systolic strain and peak systolic strain rate was measured by the combined tissue Doppler / speckle tracking segmental strain application of the Norwegian University of Science and Technolgy, but the results were compared to other methods in a subset of subjects, showing small differences.

The poulation had the following characteristics:

The study consisted of  673 women with a mean BP of 127/71 ,mean age of 47,3 years and BMI of 25.8 and 623 men, with mean BP of 133/77, mean age of 50.6 and BMI of 26.5. Both sexes were normally distibuted with an SD of 13.6 and 13.7 years, respectively. 20% of both sexes were current smokers.

Ordinary echo findings were:
Mean
 Female
 Male
IVSd (mm)
 8.1
 9.5
LVIDd (mm)
 49
 53
LVPWd (mm) 8.2
 9.6
FS (%)
 36
 36
Mitral E (cm/s)
 75
 66
Dec-T (ms)
 218
 238
IVRT (ms)
 93
 103


These findings are in accordance with other studies, like the findings of Schirmer et al (156, 157), so the study population may be assumed to be representative.
The study showed strain and strain rate to be normally distributed.
The study shows little differnce between different levels (basal / midwall / apical), or between the different walls. Although some differences were statistically significant, the differences were so small as to be clinically insignificant.
The tables of normal values are given throughout the text:



Before using any specific method, there are thus some caveats:


Deformation imaging has a high variability, and the variance means that some of the findings are artificial. This also means that it is possible to achieve almost the results one wants, as changes are small from one point to another as shown in the example below, traces that seem reasonable, may still be artificial. In choosing to accept or reject such curves, they may be accepted or rejected according to 2D information, thus resulting in biased post processing,  giving the result that are expected, but this does not add information. It is equivalent to using a lamppost as support, rather than enlightenment.


Albert Engström 1869 - 1940


However, this is not specific to deformation imaging alone. During an integrated, comprehensive echo examination, the integrated approach always includes wieiighing the single findings against the totality, resulting in changing the interpretation or dicarding some measures as being inconsistent with the whole.

This is relevant both in clinical practice, but also in studies. Given the high number of artefacts found in daily echo practice, studies reporting a very high feasibility may be prone to this effect. This means that not only do the studies overestimate the accuracy of deformation images, by just confirming the visual assessment, but the wall motion may in fact be the main sorce of information. However, studies reporting added information or increased accuracy in relation shows the added diagnostic value, as has been shown in some studies (128, 133). But basically a high discard rate ensures higher quality of the studies.

In the following, I have tried to give some rules to avoid falling in this trap.


1:The fundamental emphasis should be on image quality.

The garbage in - garbage out principle still is important.

A: This means that sub standard segments should not be included, even if the curves seems reasonable, segments with poor data quality should be discarded entirely. Presence of drop outs, reverberations and poor alignment should result in the segment being discarded from analysis before going on to post processing. Remember that even with good visibility of movement, shadowy reverberations may be present overlying the moving grey scale image. Look carefully.

B: Any completely unreasonable curves should be discarded outright, even if the segments are accepted in the first place.

It is important to remember that image quality may affect different modalities differently. Especially visual assessment may be sharper than ultrasound, as the visual acuity for movement is better than for stationary structures. Thus, shadowy reverberations may seem less serious by eyeball assessment, compared to the impact both on tissue Doppler and speckle tracking. The parametric images is useful for assessing image quality in TDI and parametric images should always be interpreted before analysis of waveforms.




Image with shadowy reverberations. The 2D image doesn't seem too bad, as the movement of the wall is fairly well visualised.
Strain rate in the same image.  Shadowy reverberations are better visualised in this image.
Curved M-mode from the lateral wall. Apex on top, base at the bottom. The S, e and a phases can be seen, but that is about all the information that can be extracted. The most important information from this image, is that the whole wall should be excluded from quantitative analysis.




By first glance, this image seems to have OK image quality. The endocardium seems well defined around most of the wall. However, the lateral wall shows good definition mostly in the latter half of the cycle.Ans shadowy reverberatins can be seen in both base and midwall.
And the TDI image quality is poor in the lateral wall, showing heavy reverberations, the effect being more pronounced due to the poor imaging of the myocardium in systole.  But even so, in parametric imaging the delay of the lateral wall in comparison to the septum is visible due to the robustness of parametric imaging.

In speckle tracking, the emphasis should be on the tracking itself. In 2D strain, the problem is greateer. The curved M-mode is very smoothed, and thus, reverberations may not be as apparent. The tracking of the points may be virtual to some degree. The automated quality control will not identify the curvature effect, and may not give sufficient input if the over all image quality is poor. Thus, emphasis should be on:
    - Excluding areas with reverberations (segmetns on both sides), irrespective of whether the values look meaningful.
    - Excluding the apex in foreshortened images, and also other areas of hgh curvature may be viewed critically.

2:Consider the limitations of each method.

In tissue Doppler, concerning angle deviation, the main point is to exclude segments with to great angle deviation from analysis, at least other than parametric.

Strain rate is a method with a high variability due to a high noise content and high susceptibility to artifacts. Some are common to all ultrasound methods, but may result in different pitfalls in different methods. A working knowledge of all problems and pitfalls is necessary to do proper post processing as well as interpret the findings.

Then, TDI and speckle tracking has different limitations, and within speckle tracking the segmental strain and the 2Dstrain again have method specific pitfalls. This means that processing may produce artifacts. The artifacts may mimic or mask  pathology, and if findings are processed to support a foregone conclusion, the result will be biased post processing.



This is the same image as shown above. Strain rate curved M.mode (left), strain rate traces (middle) and strain traces (right) from the same cine loop with a stationary reverberation in the lateral wall.  The reverberation is easily identified in the M-mode, and the timing of the phases of the heart cycle is evident despite the reverberation. Thus, the curved strain rate M-mode is useful even in the presence of fairly severe artifacts, especially for timing. In the traces, the yellow curve shows dyskinesia, the cyan shows hyperkinesia (in strain rate), the red is apparently normal, and the green shows initial dyskinesia and then some shortening. From the traces alone, it's not possible to identify what's correct. Thus, any attempt to use the curves to determine what is correct, will result in getting the answers you want. Even the normally appearing curve (red) should be discarded.  The image shows also clearly how meaningful information can be taken from the parametric image (curved M-mode), both in terms of identifying the artifact as well as the timing and phase information. The mechanisms for the artifacts is discussed above.

Thus, in areas with poor data, the traces will depend on position of ROI. Both apparent pathology in normal areas as seen here, and in the limitations paragraph and apparent normal function in pathological areas may be produced. Trying to eke out meaningful curves from poor quality data, and accepting those you find reasonable will result in biased post processing. Another example is shown in the effects due to the reduced lateral resolution of tissue Doppler. 



3: The more processed data are, the more prone to errors.

It is an advantage to try and get as much information from the least processed data as possible. In this case it means always start to look at the velocity curves, which always will give much information about deformation as well.

The stiffness of the inferior wall is evident, all three motion and velocity curved lie on top of each other. This is the same information as displayed in the parametric image above right. In this instance tissue Doppler serves to confirm the question of wall stiffness.  There are normal basal velocities (6 cm / s) and displacement (12 mm), indicating that there is apical hyperkinesia compensating for basal akinesia. There is in addition diastolic abnormalities with a delayed and reduced E-wave. In this case, the main deformation is evident without processing to deformation data. Haowever, deformation data will give additional information, as shown below. But this basic approach is less vulnerable to artifacts.

Tissue velocity gives increased temporal resolution, and will show presence of synchrony / asynchrony, presence of post systolic motion and diastolic function. Data are quantitative. Displacement shows more or less the same as velocity, but mainly in systole. Also look at the difference between the curves from basal, midwall and apical segments, to see if the velocities decrease in an ordered way, (i.e. the velocity gradient being evenly distributed). Strain rate is the spatial derivative of velocity, and has increased spatial resolution compared to velocity. It will discern better between hypo- and akinesia, and give a more precise location of pathology. If there is much random noise, integrated strain will eliminate this, but still give the same spatial information.

Unreasonable results, even if the curves are within the possibility, should still be carefully assessed before being accepted. This is the tricky point, as this may introduce bias. In this case, the parametric images should be assessed as well, to see whether the finding shows up in the semi quantitative plot:

4: Colour images reduces quantitative data to semi-quantitative, which are more robust.

 This will increase robustness, and will also show:
    - If abnormal findings have a spatial extent, thus not being a finding of only one point. A curve that changes much from one pixel to the next, is unreliable, as shown above.   although especially drop outs have spatial extent as well as seen in the methods limitations paragraph).
    - If timing of regional events is affected
Both being necessary conditions for the abnormal finding to be real.

In my opinion the curved M-mode should always be looked at before the traces, and WMS assessment should be done.


The colour (parametric) imaging can be translated into a wall motion scale, equivalent to wall thickening (6, 7) :


Curved M-modes from different walls. All are drawn from apex (top) to base (bottom) as shown in the paragraph on parametric imaging above. Green shows areas with no deformation.
 The timing of events indicating pathology is evident in curved m-modes.
If timing is the most important, even poor quality images can be used.
 1: On top, normal systolic function, the shortening phase (orange) can be seen as fairly even in colour and starts and ends at about the same time in all segments of the wall; WMS=1. Below that, the two basal segments are hypokinetic. The orange colour starts later, and is mottled, this is due to a lower  mean (absolute) value, in combination with variations due to noise. WMS=2 - hypokinetic. In addition, the shortening can be seen to extend into the diastolic phase; there is post systolic shortening. Below that, the two basal segments are totally green throughout systole; akinetic, WMS=3, although post systolic shortening is evident. 4: Bottom, there i dyskinesia (systolic stretching - blue) with post systolic recoil. WMS = 4. Colour SRI M-modes from septum of the same examination, showing clearly at 20 µg/kg/min the development of a prolonged shortening period in the apex,  but still systolic shortening as well. During peak stress, there is virtually no systolic shortening, only post systolic.
Curved M-mode from the whole wall of a patient with cardiomyopathia, bundle branch block and asynchrony. Even if there is a surprisingly high amount of reverberations, the ssystolic shortening of the two walls can be identified, (ellipses), and the delay of the lateral wall compared to the septum is evident.

5: The whole curveform should be taken into account, not only peak values.

There is information in the whole curveform. In ischemia, early signs are delayed onset of shortening, as well as post systolic shortening, reflecting slower rate of shortening and delayed onset of relaxation due to reduced energy, and the interaction with other segments.



Feasibility

With a liberal attitude to excluding segments, the question becomes related to the feasibility of analysis. accuracy may be as good as it will, if there is too low feasibility.  We did a feasibility study (115) at our department, showing that the there were reverberations in more than 80% of the patients. With the high number of reverberations artifacts reported, it may well be that the real feasibility should be around 80% of segments, and that studies reporting more than 90% by manual analysis may in fact have a high number of artifacts included in the data.

Attempting to isolate strain rate data from 2D information by 3-dimensional parametric imaging presented to blinded observers resulted in low diagnostic accuracy (slightly better with experienced observers). The data in this study was unfiltered, no artifacts were excluded. It would seem that the information content  of "pure strain rate data" was close to zero. Thus, without eclusion of artefacts, the informational content is low, as opposed to strain rate imaging as add on to 2D grey scale.
Recent studies with automated analysis has changed that picture, however:

In automated analysis

one uses manual or automatic placement of anatomical landmarks, such as the mitral plane and the apex, or draws a curve along the myocardium. The walls are then automatically segmented, and strain rate calculated according to the application used. This is implemented in the segmental strain application of NTNU,  as well as in the various commercial speckle tracking methods. This automatic segmentation will in itself give a better repeatability than manual placement of the ROI, without recourse to smoothing. By this method, segments are discarded due to poor tracking, poor alignment , visible presence of reverberations as well as curve quality. Automated post processing will give segmental values once the region of interest is defined, eliminating the search for suitable curves, thus resulting in more objective traces. Discarding segments with poor data quality remains the only option  in manual evaluation of results.

In a pilot study (127), the feasibility was between 75 and 80% of segments, using the automated segmentation, both with velocity gradient (in mid segment) or by segmental strain, while a little over 90% were analysable manually. This last number may be an overestimation, and an example of biased post processing, in this study. The higher feasibility of manual analysis results from the possibility of reducing ROI and strain length, trying to get useful information out of small areas between artifacts. At that time, we were more prone to accept all curves that seemed reasonable. In addition, the numbers were too small to demonstrate differences in diagnostic accuracy.

In stress echo, a study using the combined application of NTNU using both TDI and speckle tracking, did show that while WMS had a feasibility of 99% at baseline and 98% at peak stress, segmental strain had a feasibility of 86 and 79% for strain rate and strain, respectively at baseline and 84 and 77% at peak stress. The velocity gradient method had the lowest feasibility with 80% for strain rate and 65% for strain both at baseline and peak stress. The peak stress However, even with  lower feasibility than WMS, the diagnostic accuracy was shown to be higher, confirming independent diagnostic value. This was also confirmed by another study (133), showing added prognostic value to WMS of deformation measures, given a feasibility at peak stress of 93% for strain rate and 87% for strain by the segmental method.

In a method study, feasibility of segmental strain and 2D strain was between 70 and 80% of segments (151). In the HUNT study (153), on the other hand, also using the combined segmental strain, the feasibility was lower, about 60% for both strain and strain rate at rest. It should be emphasized that this, although being partially due to the limitations of segmental strain, the main emphasis in this study was to provide normal data. Due to the large number of subjects, the possibility to exclude liberally, ensuring that the result were free from bias due to artefacts, were present. Basically the low feasibility here is a characteristic of the study, not the method. This is also the main strength of the study, not a weakness as some mistakenly maintains, when they confuse study and method. That this policy did succeed, is shown in that the values are normally distributed, as opposed to findings in some other population studies.




Clinical approach:

It is evident that even if the documentation of incremental value in studies is scarce, in selected cases deformation imaging will serve as an aid to diagnosis. This depends on showing that diagnosis is equivalent, even if not necessarily better. This is equivalent to all echocardiography, no single measurement will be perfect and give the diagnosis, an echocardiographic examination is always using all the available, and more or less circumstatial, evidence, weighing it against each other and giving a conclusion, that is usually fairly certain, even if single measurements are not. The incremental value of any method, used in this way, may be difficult to document. With the reservations inherent in basic ultrasound and in the specific methods,  clinical ultrasound will be a craft, not pure science.

A few practical examples although fairly old, will illustrate the basic approach to regional diagnosis. More examples are given in the text in the main section, showing the type of curves seen in different pathology. Various examples from stress echocardiography can be seen here, diverse infarcts can be seen here, here, and here.  Colour parametric images are shown here, including an example of asynchrony is shown here.

Apical infarction:
This anteroapical infarct shown in 4 chamber is easy to see, i.e. the B-mode image shows apical hypokinesia and reduced global left ventricular function. As shown in the section on parametric imaging, the infarct can be displayed by colour, during systole (yellow ventricle, the apical infarct is blue, in diastole (blue, the infarct shows post systolic shortening).  But the moving image makes it difficult to see. (this is a different  patient than the one to the left).
Curved M-modes from base to apex, top:, velocities, bottom; strain rate, showing regional akinesia in the apical and hypokinesia in the midwall segment, all velocities in the whole wall is reduced. In addition there is post systolic shortening in the apical two segments, resulting in velocities being visualised in the basal two segments due to tethering. (This is the same patient as the one to the far left).





In motion imaging, there is evidence of reduced global function, by the reduced systolic velocity (4 cm/s) and displacement (8 mm) of the annulus. In addition, the velocity and displacement curves show little distance between the apical and midwall curves, indicating no deformation from midwall to apex. This is also evident in the tissue tracking image showing one colour (yellow) all the way from midwall to apex, indicating that the area is stiff, near akinetic. In addition, there is post systolic motion. This is evident in all levels, which probably means that the source for this is the apex, while the base moves by tethering. This demonstrates that tissue Doppler imaging gives more temporal detail than eyeballing grey scale alone.

Strain rate and strain confirms the location of  the infarct showing reduced systolic strain rate (-0.5 /s) and strain (-4 to 8%) in the apex and  midwall. It also shows post systolic shortening of another 5% (Post systolic strain rate -0.5 /s), confined to the apex. This confirms the location, suspected in tissue velocity, and locates the site of pathology. Although this was evident already from grey scale, tissue Doppler and strain rate has in addition quantified systolic deformation, showing the infarct to be hypokinetic rather than akinetic, and  showed and located post systolic shortening which was not evident by eyeballing. The post systolic shortening in the apex results in post systolic velocities in the base, due to tethering, this could be inferred by velocity, but shown directly by strain rate imaging.

Inferior infarction:

In an inferior infarct, the findings will be somewhat different.


2-chamber view of a localized inferior infarct, which is easy to see in B-mode.
 Parametric image of strain rate from the same subject as left, the infarct is akinetic (green ) in systole
and shows some post systolic shortening in diastole, but timing is not easily discerned by the moving
image, one method is to stop and scroll the 2D image, another is to look at the curved M-mode, which
is shown as WMS3 above.



In this 2-camber view of a different infarct, there is motion, although with some experience it is evident that the inferior wall is stiff, moving as one piece. This of course, means no deformation, and thus akinesia. In some instances this may not be so easy to see, and here tissue Doppler is particularly helpful. Tissue tracking demonstrates the systolic stiffness in one single image, (The whole wall moves as one piece) but with less spatial resolution and only the systolic information.
The stiffness of the inferior wall is evident, all three motion and velocity curved lie on top of each other. This is the same information as displayed in the parametric image above right. In this instance tissue Doppler serves to confirm the question of wall stiffness.  There are normal basal velocities (6 cm / s) and displacement (12 mm), indicating that there is apical hyperkinesia compensating for basal akinesia. There is in addition diastolic abnormalities with a delayed and reduced E-wave.




In strain rate imaging further details are seen: Basal dyskinesia, midwall hypokinesia, both with post systolic shortening and normal apical function (high normal). In the curved M-mode from base to apex, top:, velocities, bottom; strain rate, showing regional akinesia (the mottled appearance is due to noise) in the two basal segments, the velocities does not show this, due to the tethering effects, the akinetic base being pulled along by the contracting apex.In tissue velocity there was no evidence of the basal post systolic shortening, which became visible only in strain rate imaging.


The later example is a perfect example of tethering, the stiff inferior wall moving due to the contraction of the apical segment.




As these examples show, the use of velocities alone does not differentiate normal and pathological as well as deformation parameters, unless the spatial relation between velocities are taken into account. But this is exactly what is quantified by deformation imaging (motion per length unit). It has been shown that strain rate imaging improves recognition of infarcted segments, compared to velocity alone (40, 41).


Bull's eye and three dimensional reconstructions of a ventricle in systole (top), showing an area of dyskinesia (blue) in the apex, and diastole (bottom), showing a larger area of post systolic shortening (yellow). Bulls eye from systole and early diastole (top, left) , below 3D reconstruction (bottom, left) in systole and M-modes from all six walls (right), showing an inferior infarct with slight dyskinesia and more extensive akinesia in systole and post systolic shortening in the infarcted wall.

Clinical evidence

It is no doubt that the methods have lead to a deeper understanding of both physiology and geometry of myocardial mechanics, as the present website attempts to show. However, the clinical utility relies on documentation in clinical studies.

In diagnosis of regional dysfunction, however, the added value of deformation measurement has been less well documented.  This also needs to be established in clinical studies.

In this, last part, I will try to review the evidence from clinical trials for the different areas of application.

The clincal evidence may be dealt into phases, analoguous with the phases in clinical trials.

  1. Phase 1 is validation and feasibility. Establishing of the validity of a new method compared to a reference method (e.g. infarcts vs. LGE MR, or Stress echo vs. coronary angiography), and how many patients or segments it can be used on. Finally, primary establisment of the methods reliability (meaning either reproducibility or variability, which are inverse measures). Also, showing the significance of difference between groups falls in this category, it says nothing of the clinical utility.
Target shooting with two different weapons. The weapon on the left shows a high reliability, as the shots are well gathered. However,  the whole group and hence the average is off centre, thus the method has less validity. The weapon on the right  shows better validity, as the average of the shots are on centre, but the shots are less  well gathered (more scattered), the weapon will tend to hit in a more different location each time, it is less reliable, the placement of the shot is more variable or less reproducible. Comparison of  three different ultrasound methods for deformation imaging, against tagged MR as reference from (151); Left 2D strain, middle segmental strain by combined tissue Doppler and speckle tracking, and right strain by dynamic velocity gradient. Top row: Bland Altmann plots, bottom row scatterplots with identity line shown. It can be seen that there is a significant bias between 2D strain and MR, while the measurements are fairly well gathered together, but on the average below the identity line. The segmental method has a small bias, but this is not significant. The method is less reliable, as seen by greater scatter (and lower correlation). The method on the left shows no bias, i.e. good validity, but even greater scatter, and is clearly the least reliable.
  1. Phase 2 is Clinical utility.
    1. In this study the cut off values between normal and abnormal measures, and the resulting sensitivity and specificity is established, in a larger clinical material combining controls and patients. Usually against an external diagnostic reference method or established diagnosis, and usually also in comparison with established methods. The sensitivity and specificity are measures of a tests discriminatory ability.


The test is:
The condition is
Present
 Absent
 Sum
Positive
 True positive (Tp)
 False posisitve (Fp)
 All positive (Tp + Fp)
Negative
 False negative (Fn)
 True Negative (Tn)
 All negative (Fn + Tn)
Sum
 All with condition (Tp + Fn)
 All without condition (Fp + Tn)
 All (Tp + Fp + Tn + Fn)
Sensitivity is the  percentage of patients with condition who have a positive test test, i.e. sensitivity = Tp / Tp+Fn.
Specificity is the percentage of subjects without the condition who have a negative test, i.e. specificity = Tn / Tn+Fp
Diagnostic accuracy is the number of true tests as proportion to all tests, i.e. accuracy =  Tp+Tn / Tp+Fp+Fn+Tn
Sensitivity, specificity and accuracy are properties of the test itself.


This is usually more related to a methods reproducibility that to its validity. Even if measures are off compared to a reference method, reference specific normal values may be established. However, there is a trend to be little comparison, just research into what is new and "sexy". If new methods prove to be better diagnostically than established methods, this is proof enough of added value.  If this is not established , for instance in prognosis, the value of adding a method tho others may be shown statistically, as for instance as done in (133).

The interpretation of the results, however, are dependent of the pretest probability of disease; i.e. the prevalence of the disease in the population that is examined.
Positive predictive value is the probability of having diease given a positive test: PPV=True positive/all positive=Tp/(Tp+Fp)
Negative predictive value is the probability of being healthy, having a negative test. NPV=True negative/all negative=Tn/(Tn+Fn)
This means that for a given test with sensitivity and specificity of 90%,
Applied to 1000 persons with a prevalence of 50%; There will be 50 Fp and 450 Tp, 50 Fn and 450 Tn; PPV will be 90%, NPV 90% (as opposed to 50% pretest)
Applied to 1000 persons with a prevalence of 10%; There will be 90 Fp and   90 Tp, 10 Fn and 810 Tn; PPV will be only 50%, and NPV will be 98%, as opposed to 90% pretest; not an impressive increase.
Applied to 1000 persons with a prevalence of   1%; There will be 99 Fp and     9 Tp,   1 Fn and 891 Tn; PPV will be 8%, and NPV will be 99.8% as opposed to 90% pretest.
    1. Establishment of normal values in a population study. Normal values may be different from the cut off values between a selected patient and reference poulation, as shown above.
  1. Phase 3 is outcome studies. Even if better predictive value for clinical events can be inferred from better sensitivity and specificity, this is not proof. Different methods may measure different things, so that, even if they correlate, will have different predictive value. Thus, the outcome prediction in clinical trals is important. The outcome may f.i. be prediction of an occluded artery, or it may be clincal events or death. Ideally this should be done in clinical intervention studies where more than just EF is included as clinical characteristics, and where the predictive value of newer methods is compared to the more establised ones. In fact, the main reason for using EF at the present day, instead of the better long axis measures, is the weight of evidence. Too many new studies of intervention are started with only EF as a reference method, due to the fact that interventional groups often lack knowledge of echo.
  2. Phase 4 is hypothetical. Ideally it should be proven that the use of a diagnostic method improves the patient's prognosis. This is almost toally lacking in all kinds of imaging research, and may be near impossible to achieve. Such studies requires large numbers, and are thus expensive, and should be applied to a integrated method, rather than specific applications. The closest we will come, is probably intervention studies where the requirements for the intervention is some kind of new or improved imaging.
However, in interventional research in cardiology, there is almost always an element of imaging, and the requirements of modern imaging research regarding phase 3 (and 4) studies should be taken into account in the study design. Only adding to the total database will serve to improve the predictive value of echocardiography with introducing newer methods with better predictive value into the clinical practice. A glaring example is EF, there are far better predictors today, but none linked so massively to intervention. This results in EF still being used as indication for intervention, despite it's shortcomings.

Any new method, arriving in to phase 2, should always be comapred to older methods. The added value of a new method is basically depending of better accuracy (phase 2) or better predictive value (phase 3). As discussed above, even if a metod is only just as good as older methods, it may be an alternative in selected patients, as well as part of the total information in an intgegrated evaluation.


It is a well known phenomenon of medical litterature that as new methods are investigated, they tend to show better results than older methods, not so much because newer methods have better accuracy, as because older methods perform poorer in new studies.

Hmm; do I smell something fishy?

The causes of this are various, there may be a publication bias in favor of newer methods, the acquisition are often optimised in favor of the newer methods, and the patients selected for good image quality in newer methods. A classical example is the studies of stress echocardiography, where harmonic imaging increased sensitivity of stress echo, compared to fundamental imaging (104, 105), but the sensitivity of fundamental imaging decreased, compared to an earlier study by the same group (103). In this case, the reasonable explanation is that with fundamental imaging, more patients with moderate image quality are eligible for stress, while yielding poor results in fundamental imaging. Thus, even if new methods should be shown superior, this may not be the over all result in daily clinic. Clinical studies should also be viewed with this in mind.

Global functional systolic measurements

Ischemic heart disease is the main cause of regional dysfunction, and thus the main target of deformation imaging, however, deformation has led to the concept of normalised measures for global function as well, which may become increasingly important in the future.

Global functional measurements by longitudinal annulus displacement and velocity, as well as global strain, have all been shown to be better discriminators and prognosticators than other measurements of global function (FS and EF). The annular displacement has been shown to be more sensitive than EF in predicting events in heart failure (36, 192) and hypertension (193), indicating that it is a more precise measure of systolic function, that the cavity measurements. This may be due to the shortcoming of EF in small ventricles / hypertrophy. It has also been shown to be a better correlate for infarct size than EF (150). Also, the MAE correlates better with BNP in heart failure, than the fractional shortening (204).

Thus, the MAE is a more all round useful measure of longitudinal function than EF.

In fact, the main reason for using EF at the present day, instead of the better long axis measures, is the weight of evidence. And alas, interventional studies using echocardiography as secondary outcome, persists in using only EF, instead of including newer measures for direct comparison of the ability in predicting clinical outcome as well as establishing cut off values for intervention.

The systolic peak annulus velocity S' has been shown to be sensitive for reduced function in relatives who are mutation positive, of patients with manifest hypertrophic cardiomyopathy, despite having normal EF and no hypertrophy (203). The diastolic functionby tissue Doppler was similarly decreased. It also correlates better with BNP in heart failure than the fractional shortening (204).

Thus, the peak systolic annular velocity is useful in that it is a better marker of systolic function, and that it offers a measure that allows direct comparison of systolic and diastolic function.

In addition, it is emerging evidence that global strain, adds incremental value to the simple AV-plane motion. This compensates for the shortcomings of ejection fraction, being both more correct in the case of small or hypertrophic ventricles, and more sensitive (149, 150, 159). This is credible, some of the variability in MAE will be due to differences in LV size, and normalising will remove this variability and give a tighter relation to pumping parameters normalised for body size, and thus a higher diagnostic discriminatory value. This probably has most importance when normal variations in body and heart size is biggest (as in children) and least importance where normal variability is lower, and variation between normal and pathological is great (as in dilated heart failure). None of the methods for normalisation, however, have established superiority. The Global strain, in one or other form, is likely to take flight in the near future.

Normalisation of velocities seem less established, systolic velocities are related to diastolic.

In the study of Thorstensen et al. (154), the reproducibility (inter observer, repeated acquisitions as well as analysis) of the different global measures was as follows: 

 Mean value (repeated measurements)
 Coefficient of repetition (2SD of difference between repeated measures)
 Mean error (% of mean)
EF (biplane Simpson; % pts)
 59
 7
 10
MAE (by M-mode; mm) 17
 1.6
 4
S' (pwTDI; cm/s) 9.1
 1.7
 8




Global strain (2DS; % points)
 -21
 2
 6
Global strain (Averaged from segm strain by combined ST and TDI; % pts)
 -19
 2
 4
Global strain rate (2DS; s-1) -1.1
 0.2
 10
Global strain rate (Averaged from segm strain by combined ST and TDI; s-1) -1.2
 0.2
 8

The coefficient of repetition is the value obtained by Bland Altmann analysis, and also represents the lowest significant difference between two measurments (f.i. repeated in one single patients). No method did show correlation of error and mean, but the mean error gives the error in percent of mean, so as to be comparable between methods giving different units. The overall ANOVA signficance of the differences in mean error was p=0.001, indicating that at least the differences between 10% mean error (EF and 2DS-strain rate) and 4% (MAE and global strain from the segmental method) are significant.

The  reproducibility of single point measurments are thus far less, as shown previously (40) where both MAE and S' increased reproducibility on the order of 25%, compared to sigle point measurements. In the study by Thorstensen, The inter observer resproducibility of pwS' was as follows:

 Mean value (repeated measurements) Coefficient of repetition (2SD of difference between repeated measures) Mean error (% of mean)
S' (pwTDI; mean of 4 points)
 9.1
 1.7
 8
S' (pwTDI; mean of septal and lateral; cm/s) 9.2
 2.3
 11
S' (pwTDI; septal; cm/s)
8.4
 2.9
 13
S' (pwTDI; lateral; cm/s) 10.1
 2.1
 9
S' (pwTDI; inferior; cm/s) 8.7
 2.8
 15
S' (pwTDI; anterior; cm/s) 9.3
 2.7
 12
Variability of S' when taken as mean of four, two or single points. It is evident that taking the mean of septal and lateral gives the same mean value as four points, but the variability is higher, mean error 11 vs 8% (althpugh borderline significant p= 0.11).  However, the corrsponding reduction for e' was from 15 to 8%, (p<0.001). The overall reduction in mean error between one point and 4 poiont mean average was also significant.

Ischemic heart disease

Ischemic heart disease is the main cuse of regional dysfunction, and thus the main target of deformation imaging, however, deformation has led to the concept of normalised measures for global function as well, which may become increasingly important in the future.

Myocardial infarction.

Ischemic heart disease is the main cause of regional dysfunction, and the first area for research. In fact, the B-mode wall motion score index, is the first assessment of regional function:

  1. Normal
  2. hypokinetic
  3. Akinetic
  4. Dyskinetic
However, analysing the wall motion by B-mode, the frame rate is higher than the temporal resolution by visual inspection (24). In order to achieve optimal temporal resolution, it is customary to stop the loop and scroll through it frame by frame. This usually shows segmental dyssynergy as failure to thicken during the first frames of each systole. But this again means that wall motion scoring is more dependent on early failure to thicken/shorten, i.e. the timing of onset of contraction, than on peak thickening/shortening (strain) or peak thickening/shortening rate (strain rate). This means that the methods in fact doesn't measure exactly the same thing.


Global measurements

Wall motion score index (WMSI), being the  average of wall motion score  of all evaluable segments becomes a measure of  global function, and has been shown to correlate with EF in infarcted ventricles (40). However, the index is useless unless there is regional differences. Any dilated cardiomyopathy will show hypokinesia in all segments, giving a WMSI of 2, regardless of EF.

For global measure, the main emphasis in publications has been on global strain, especially by the 2D strain application. However, global strain may be obtained by any method by averaging the segmental values, which will give reduced variability as well as shown by Thorsensen et al. (154). There  was ano difference between 2Dstrain and segmental strain by combined ST and TDI, for global measures. Basically, global functional measurements should be expected to show reduced function, with increased infarct size. This is shown for WMSI as well as EF, and also that they correlate (40). However, it's only after the advent of MR, that we had a reliable method for quantitating infarct size independently, enzyme markers being unreliable, relating as much to the degree and timing of reperfusion as to infarct size.

Global strain was shown to correlate well with infarct size (R= 0.84), as compared to WMSI (R= -0.71) and EF by echocardiography (R= 0.58) (205). The diagnostic accuracy for infarcts => 30g by ROC analysis was AUC of 0.95 for global strain (giving a sensitivity of 0.83 and a specificity of 0.93 ), 0.90 for WMSI and 0.81 for EF.The study is hampered by not giving confidence intervals, thus not showing whether the differences between methods were significant. Another study by the same group did show a trend towards improved accuracy in infarct diagnosis by global strain, compared to MAE, EF and WMSI (150), but again without any confidence intervals. Also, normalising for infarct size did not seem to add to the value of MAE in adults. Perhaps because the range in LV size is small.

2D strain has been applied to early echo in NSTEMI. It has been shown that global longitudinal strain correlates with final infarct size (189), and was a far better predictor than EF, but so far, no better than WMSI.

Regional measurements



It must be emphasized that while global measurements are averages over the whole ventricle, and thus more robust and reproducible, the segmental measures are from one segment only, and thus has a higher variability. (Unless one applies smoothing,, of course, but smoothing is indiscriminatory, and will smoothe away real differences just as much as differences due to method variability. We compared the reproducibility of single segment measurements and global averages (154):
Mean value (repeated measurements) Coefficient of repetition (2SD of difference between repeated measures) Mean error (% of mean)
Segmental strain and strain rate
 Global strain (% points)
 -19
 2
 4

Global strain rate (s-1)
 -1.2
 0.2
 8

segmental strain (% points) -19
 8
 18

segmental strain rate (s-1) -1.2
 0.5
 16
2D strain Global strain (% points) -21
 2
 6

Global strain rate (s-1) -1.1
 0.2
 10

segmental strain (% points) -21
 7
 14

segmental strain rate (s-1) -1.1
 0.5
 17
The variability of segmental values that was 2 - 3 times higher, compared to global values (p<0.001), but for regional measures, there  was no difference between 2Dstrain and segmental strain by combined ST and TDI

Thus, averaging more than one segment reduces variability. However, as discussed in the main section, segmental values cannot be averaged for a whole wall, due to the segment and AV plane interaction. However, there is possibility to average segments withing a vascular territory, as discussed below.

Unless there is definite proof that quantitative measurements is better than WMS, the alternative to quantitative measurements is simply to use the parametric WMS from strain rate, this reduces the information content, but also the variability. In addition, it will make it possible to measure timing of evennts as time to segmental onset of shortening, as well as time to onset of lengthening (which is an indication of post systolic shortening)(186).

Wall motion scoring by colour SRI:


Colour WMS by SRI, Curved M-modes from apex to base. This is more explained above.

Using curved M-mode colour display for wall motion scoring, WMS by colour strain rate imaging was shown to have fair correspondence with B-mode (6) kappa 0.45, weighted kappa of 0.63, to 0.64 (7). For repeated measurement, both inter- and intra observer, the weighted kappa was of the same order of magnitude, also for the WMS by B-mode. It was also shown to have similar accuracy in diagnosing regional coronary disease (7, 10) with a sensitivity of about 70%, a specificity of 90%, and an overall accuracy of about 84%. Interestingly, adding the two methods did not change the overall accuracy, indicating that the methods gave the same information (7). (NB: strain rate was evaluated unblinded to B-mode loops). Another study (10) concluded that both strain rate and strain could describe regional dysfunction in infarction, but the variability in this study is about the same as in the others, so the overlap in values between segments with different WMS is too great for the method to be clinically useful in the individual patient, although the numbers needed for significance in those studies was quite low (10 - 25 patients).  Strain by ultrasound did show a fair correspondence with strain by MR in another clinical validation study (9), showing fair correspondence, with no significant bias, but with limits of agreement about ± 7%, as compared to normal strain of 18% in controls and 15% in remote segments in infarction patients. In this study mean strain in infarct segments was 1-2%, showing that only akinetic segments was considered, and with a repetition coefficient of 7%, hypokinesia may be difficult to separate from normokinesia. A comparative study (40), of ring motion by M-mode and tissue Doppler vs segmental analysis by peak systolic strain rate showed that neither ring velocity nor displacement could identify the infarct site in terms of myocardial sector affected, while segmental analysis by strain rate could. However, this was also only by significance for group data. The interesting point was that mean strain rate of a sector could not identify the infarct site either, although segmental strain rate could, showing that infarct distribution is not limited to  discrete sectors.

In conclusion, parametric strain rate imaging seems to have a sensitivity and specificity comparable to grey scale imaging (about 85%), both in locating infarct segments and in semi quantitative analysis of wall motion. Repeatability also seems to be on the same magnitude. In quantitative analysis, careful post processing may give a sufficient precision for clinical work. One of the regions that are difficult to assess visually, is the basal inferior wall, as this region may have a lot of motion, but little actual contraction, as shown above.

Quantitative measurements

Quantitative measurements have shown better ability to discern infarcted from non infarcted segments, than velocities (40, 41). A study comparing segmental velocities to segmental strain rate (41),  concludes that peak systolic strain rate is superior to segmental peak systolic velocities in identifying infarcted segments, against M-SPECT fixed perfusion defects as reference. Sensitivity and specificity for recognition of infarct segments were 91% and 84% for colour SRI, 63% and 73% for colour DTI, 78% and 71% for B-mode echocardiography (WMS), and 87% and 77% for anatomic M-mode (AMM), respectively. Repeatability of evaluation of infarcted vs non infarcted segments was 0.85 with both colour DTI and colour SRI, but with higher sensitivity and specificity of SRI. Colour analysis was considered feasible in 100% of segments. The results are similar to previous studies. In quantitative analysis, peak SR was measurable in 84% of segments, while peak segmental velocity was feasible in 91%. Peak SRs correlated with wall-motion assessment by B-mode echocardiography better than peak velocities (R = .66 vs.10), with less overlap between groups, but still the study showed overlap between peak systolic strain rate in segments grouped by grey scale WMS. The variation (SD of  differences) were reported as 6 - 10% or 0.04 to 0.06s-1. This corresponds to a repetition coefficient of  0.10s-1, which is quite acceptable. This study was done by averaging measured values from three cycles. It would seem to add information by SRI to WMS.

Basically, segmental reduced function will not cause the ring to lag in part of the circumference, so much as the total ring motion will be reduced as a function of the reduced total shortening force (40). This may explain why the global strain is just as useful as regional strain in assessing the infarct size, due to the segment interaction and the interaction with the AV-plane.

The acute phase of myocardial infarction may be considered as an acute ischemic event. However, several studies has addressed the presence of acute ischemia in other settings. Kukulski et al (99) did a study during PCI, demonstrating a reduction in peak systolic velocities, strain rate and strain in both longitudinal  (LAD occlusion) and transmural (RCA/CX occlusion) direction. SR and strain had the highest sensitivity / specificity (75% / 80% and 80%, respectively) compared to 68% / 65% for velocity in identifying ischemia. In ROC analysis, the AUC was 0.62 for reduction in systolic velocities, 0.84 for strain rate and 0.82 for strain. The main implications of the study is that it demonstrates the difference in sensitivity of deformation vs. motion imaging, due to tethering effects. As strain rate is more noisy than velocity, the repetition coefficient may well be substantially higher, and the clinical value similar.

Quantitative measurements have also shown the ability to quantitate changes in regional function during the recovery phase of an acute infarction, showing that there is a rapid recovery already the first 1 - 3 days, less during the first week (92, 174, 188). One example is shown above.In the last study, there were little reduction (compared to normal) in global indices (including annular plane parameters and global SR and strain)  the first day, and subsequently little improvement during the first week. Infarct related segments, however, had a WMS of 2.7 the first day, improving to 2.4 the second and third and 2.2 the seventh. (Decimals due to the averaging.)

Contrary to this, train rate and strain improved most on day 2, less from day 2 to 7.
Day 1
 Day 2
 Day 7

Mean WMS in infarct related segments
 2.7 (0.4)
 2.4 (0.7)
 2.2 (0.7)
Segments with severly depressed function
 Strain rate (s-1)
 -0.24 (0.2)
 -0.92 (0.5)
 -1.2 (0.4)

Strain (%)
 -1.4 (1.7)
 -11.6 (5.5)
 -14.7 (6.5)
Segments with modeately depressed function
 Strain rate (s-1) -0.6 (0.06)
 -1.0 (0.3)
 -1.1 (0.4)

Strain (%) -7.7 (1.1)
 -14.7 (4.1)
 -15.1 (1.1)
Standard deviations in parentheses.

From this, it's evident that peak strain rate and strain are near normalised during the first week, but not WMS. The authors argue that this shows that strain and strain rate are more sensitive to changes than WMS. This is true, insofar as the main purpose is to differentiate between stunning and necrosis. However, this need not mean that WMS is less sensitive, as argued above, WMS as analysed by early systole may reflect timing more than peak thickening, at the time course of recovery may be different between delayed onset and  peak contraction. But this difference will make peak systolic deformation the earliest predictor of functional recovery, and may be more useful in early assessment.




The presence of post systolic shortening (PSS) in acute myocardial infarction was observed by Jamal et al . (91) and might represent another diagnostic criterion. This was addressed in a longitudinal study (92) showing the presence of post systolic shortening in 60% of infarct segments (73% of mid infarct segments, but in all patients), 29% of the border zone segments and 5% of presumed non infarct segments.  The finding that the area of  PSS exceeds the area of hypokinesia was also observed in a study of 3D parametric imaging of myocardial infarction (22). PSS disappeared in virtually all border segments in one week, and half the infarct segments after 3 months. Thus PSS has neither the sensitivity nor the specificity of identifying infarcted segments, and the presumed ischemic border one also does show PSS, but it may be important in identifying acute ischemia, and in identifying infarct segments in combination with peak strain rate /strain. Post systolic shortening has been shown to be present in 30% of normal segments, but in those cases always in combination with normal systolic strain (97). The best cut off between normal and pathological PSS was considered post systolic strain > 2,5% absolute or 2=% of total strain. In patients with acute ischemia, PSS was present in 78% of ischemic segments and 40% of non ischemic segments, in scarred segments the percentages was about the same. The last finding contrasts with another study, where PSS was reduced both in magnitude and extent from the acute (1 day) to the chronic (3 months) phase of myocardial infarction (92).

The study of Kukulski et al (99) by post systolic shortening, the AUC was 0.67, 0.80 and 0.85, respectively, for increase in post systolic velocity or strain rate /strain, demonstrating the diagnostic value of post systolic shortening in ischemia. This study also showed the reversal of post systolic shortening after reperfusion. On the other hand reproducibility data are not given. The other main point of the study is that the presence of post systolic shortening  is established as an important marker of acute ischemia in a clinical setting being present after very few seconds. As the duration of ischemia is short during PCI, however, the reversibility may not be the same after prolonged ischemia (stunning) or myocardial infarction (92, 97). The clinical setting was such that it has more important bearing on the method and the pathophysiology than the actual clinical utility.

This is further developed in another paper by the same group (100), where the post systolic strain index is defined as PSI = (peak  strain - end systolic strain) / peak strain. As ischemia is shown to induce reduction in systolic strain as well as increase in post systolic strain, the combined index was shown to be more sensitive, AUC of 0.95 with a cut off value of 0.25 giving a sensitivity and specificity of 89%, as compared to 0.84 for end systolic strain alone (cut off -10%, sensitivity/specificity 86/83%). Repeatability is not given. Newer studies have fond lower accuracy of PSI ( 205). In stress echo, the post systolic index has not been shown unequivocally to give added diagnostic value (128).

However, the concept of post systolic shortening is basically an expression of inequalities in systolic relative load, and an indirect measure of delayed contraction.

Longitudinal strain and strain rate with tissue Doppler has been shown to correlate with the transmurality of infarction in myocardial segments (210, 220), with late enhanced MR as reference. Difference was shown to be significant with strain for segments with > 25% transmurality of scar, for strain rate with > 50% transmurality. However, overlap was present, and sensitivity and specificity data are not given. It is also doubtful, whether the fine division of transmurality into four categories is useful despite the findings of Kim (211). Longitudinal strain and strain rate is still a functional measurement, which may be more important than the anatomical information given by the MR. The findings of reduced strain with increasing transmurality has been repeated, although the diagnostic capability was no better than WMS ( 205). The difference in longitudinal strain between subendocardial and transmural infarcts by 2D strain was not shown in another study (221), thus it may still be a difference in sensitivity between the methods.

Analysing strain in terms of vascular territories, i.e. averaging the segmental values over a classical vascular territory, reduced the confidence intervals, showing an improved reproducibility by averaging segments. This is in line with the findings above, that reproducibility of segmental values is far poorer than global averages. This reduction in variability also improved accuracy (significantly??), both of strain and WMSI (205). In that study, however, the newer view of overlap of vascular territories (146), as shown above, has not been taken into account, which may limit the availability of segments to average, especially in circumflex.

2D strain

has also been shown to give quantitative information about the degree of myocardial loss. Global strain correlates well with infarct size as discussed above.

A recent study have compared tissue Doppler derived longitudinal strain with speckle tracking derived 2D strain in diagnosis of myocardial infarction (213). Strain did show a significant improvement from the acute phase to discharge, however, the significance of this finding was limited to tissue Doppler derived strain, while neither longitudinal nor circumferential 2D strain could shown significance. This may be an indication of lower sensitivity by this method, which may be related to the smoothing issue.

Both methods were able to discern between non infarcted, sub endocardially infarcted (1-50% scar) and transmurally infarcted segments (51 - 100%), as was circumferential 2D strain. The AUC was the same (0.75) for longitudinal Doppler and 2D strain, while circumferential 2D strain  had AUC 0.85, again it is not clear whether this difference is significant. Global Doppler and 2D strain had probably no significant difference in ability to discriminate large (>20% of infarct mass) from small infarcts (AUC 0.85 vs 0.88).

However, when looking separately on apical and inferior infarcts, it seemed that the longitudinal Doppler strain was the only longitudinal method separating non transmural from transmurally infarcted segments, while the results for longitudinal 2D strain did not reach significance. For inferior infarcts, the separation between normal and sub endocardially infarcted segments was borderline significant by both methods, in apical infarcts 2D strain was not significant. This may be due to the increased curvature dependency in the apex; look at the small apical infarct in the main section. Another study comparing longitudinal and circumferential strain by 2DS, did not find differences in longitudinal strain between sub endocardial and transmural infarcts (221). This may not be the real case, but simply express the difference in sensitivity between 2DS and tissue Doppler.

Reproducibility was good by both methods, slightly better by 2D strain, which is to be expected, as only speckle tracking was processed by the smoothed 2DS strain method.

In the setting of acute myocardial infarction, the STEMI is readily identified, and should preferably be selected to immediate invasive treatment. IN NSTEMI, there is a substantial proportion of patients with occluded infarct related artery (IRA), which may hypothetically profit from the same immediate invasive treatment. The identification of these, might be useful. 2D strain has been applied to early echo in NSTEMI. It has been shown that global longitudinal strain correlates with final infarct size (189), and was a far better predictor than EF, but no better than WMSI. The extent of the area at risk in terms of number of dysfunctional segments, has been shown to be related to the presence of occluded IRA (218). The number of dysfunctional segments were larger by longitudinal strain than by WMS, presumably because of better sensitivity, thus adding to the emerging indications that quantitative deformation measurements may add some information. However, this was not confirmed in another study by the same group (219), where longitudinal strain by vascular territories was no better than WMS in predicting occlusion, while circumferential territorial strain by 2DS was better. Thus, this may still be considered somewhat unanswered.

Transmural and circumferential strain:

Transmural and circumferential strain must be analysed in cross sectional views, and can only be analysed by speckle tracking. Tissue Doppler may give transmural strain in the anterior and inferior segments (crosswise), and circumferential strain in the lateral and medial segments (tangentially).

In a study by Becker et al (212), 2D strain was used to measure transmural and circumferential strain in short axis. They did show a reduction in transmural and circumferential strain with increasing transmurality, but still 11% transmural and 8% circumferential strain in transmural infarcts (50 - 100% transmurality), and with standard deviations of 5 - 7% for transmural and 8 - 10% for circumferential strain, the overlap was considerable. All differences were significant, but the sensitivity and specificity for separating non transmural (1 - 50% scar) from transmural (50 - 100% scar) was about 70% for both strain components, and even slightly lower for separating non infarct from non- transmural infarct. The authors argue that the method is less noisy than tissue Doppler, without showing any comprehension that this is due to the degree of smoothing. As shown above, the tissue Doppler curves become just as smooth when processed with the same application. Also, as we can se above, the transmural strain, and hence, the circumferential, is highly processing dependent. They also describe that strain in completely transmurally infarcted segments was not zero, and ascribes this to tethering, without any reference to the processing issues of the 2D strain application in spline smoothing, evening values between segments and ROI width determining the value of strain. The dependency of the transmural strain on ROI width may also be a factor in this finding.

In the study by Chan et al (221), the circumferential 2D strain was able to discern between transmural and non transmural infarcts, while longitudinal 2D strain was not, despite previous findings that longitudinal strain was proportional with infarct transmurality, both with TDI (210, 220) and 2Dstrain (205). Some of the effect may be method specific:
  1. As 2DS may have lower sensitivity for reduced longitudinal function due to smoothing. Thus seemed to be the case in the study by Sjøli et al (213) as well, when longitudinal and circumferential 2DS were compared.  Difference between subendocardial and transmural longitudinal strain was significant by tissue Doppler, but only circumferential strain by 2DS.
  2. The ROI may not reflect the real wall thickness, the circumferential strain is dependent on ROI thickness, and the reduced strain may not be apparent in subendocardial infarcts. 

Studying NSTEMI, in one study (219), longitudinal strain by vascular territories was no better than WMS in predicting occlusion, while circumferential territorial strain by 2DS was better, despite previous findings by the same group (218).










Stress echocardiography:
Typical dobutamine stress echo. Development of apical ischemia during stress echo.; showing normal contraction at baseline, increased during low dose (10 µg/kg/min, may be a biphasic contraction at 20 µg/kg/min, not very evident in this animation, but may be better visualised by stopping and scrolling the loop in the clinical situation. Peak dose (30 ug/kg/min, the stress test terminated because of evident ischemia) showing substantial hypokinesia in the apex.
SPECT showing reduced uptake in the anteroapexapex at rest, but worsening during stress, due to the distortion of the polar ("bulls eye") projection, the apical area is underrepresented.

Angiography findings, showing three vessel disease. The most seriously affected area probably the LAD, due to the retrograde filling from a severely stenosed vessel.

In this case, the Ischemia is evident without recourse to deformation imaging. However, this is not always the case.


The interpretation of stress echocardiography is dependent on the subjective assessment of wall thickening (eventually substituted by wall motion, meaning endocardial excursion, but this may be less specific for preserved function as segments may move by tethering). This is subjective, and provides only semi quantitative data. It has been shown to be extremely experience dependent, as trained echocardiographers with no specific training in stress echo has only a sensitivity of 65%, i. e. no better than exercise ECG, while expert stress echocardiographers has about 85% to 90%, comparable to myocardial SPECT perfusion imaging (101), as illustrated below.




 Furthermore, it has also been shown that visual assessment has poor temporal resolution, (usually about 100 ms, with training down to 80 ms), and therefore has limited ability to detect more subtle changes in myocardial function (102), although this can be compensated by increased frame rate and lower replay rate, a point not raised in the study. Inter institutional reproducibility has been shown to be low, a study from 1996 (103) did show a kappa coefficient of 0.37, sensitivity of 76, specificity 87%. Introducing second harmonic imaging increased the reproducibility to 0.69 in intra institution agreement (104) and 0.55 inter institution (105). The sensitivity was 92%, substantially better than the study from 1996, but still at the same level as reported in other studies (101). Fundamental imaging, however, did show a decrease in sensitivity compared to 1996. This illustrates a general principle, whenever a new method becomes available, the accuracy of older methods decreases. However, without fundamental imaging, more patients may be classified as non-echogenic, indicating that with harmonic imaging more patients became eligible for stress echo at sufficient diagnostic accuracy.

Myocardial velocities

Still, the method remains experience dependent and semi quantitative. Tissue Doppler has the promise of increased temporal resolution as well as quantitative and objective measurement. Peak systolic velocity is a robust measurement, as well as closely related to contractility. Peak segmental systolic velocity during DSE was shown to be reduced in segments with reduced wall motion score and segments supplied by a stenosed artery (106). This was further elucidated in a study where patients and normal subjects were compared (107). Feasibility was 92% of segments, normal values were established in the normal group, and cut off was set to give a specificity of 80%. The definition of the normal dobutamine response was set in each segment, derived from normal subjects, patients with a normal 2D dobutamine response and patients with normal coronary angiography. The study measured all feasible segments in the basal and midwall levels.  The sensitivity and specificity of systolic velocities for affected vascular territories was 83 and 72%, vs. 88 and 81% by wall motion scoring. Limits of agreement was 0.2 cm/s for inter observer and concordance 86%. Analysis was not feasible in the apex, due to the low velocity and poor depth resolution in the near field. Thus, Systolic velocities seem to give comparable results, but not better, than Wall motion scoring. However, the diagnostic accuracy by tissue Doppler was the same by novice interpreters (76%), expert echocardiographers (74%) and slightly lower than expert stress echocardiographers (6%) as compared to wall motion scoring (68, 71 and 88% respectively) (108).



Velocities were measured in the middle of each segment. Of the 77 patients investigated, 55 had significant coronary artery disease. Nineteen patients (25%) had 1-vessel disease, 17 (22%) had 2-vessel disease and 19 (25%) had 3-vessel disease. Of all the patients studied, 40 (52%) had disease of the left anterior descending artery; 33 (43%) had involvement of the left circumflex artery, and 37 (48%) had involvement of the right coronary artery. The criteria for a positive test by tissue velocity (one or more segments, how much below below the cut off limit), is not reported, but all twelve midwall and basal segments were analysed.

Another study, the multi centre MYDISE study, reported a similar feasibility but slightly less reproducibility in using the segmental velocities (109), with coefficients of variation of  11–18% for peak systolic velocity at peak stress in basal, 14–28%  in mid segments and 29–69% in in apical segments. This study also concludes that the apical velocities are too low to give reproducible results. In this feasibility study, 10 normal studies were analysed by nine different observers. Feasibility was reported to be 90% of midwall and basal segments in 92 normal subjects. In the second part of that study (110), the diagnostic value was addressed in 289 patients. Cut off values were established by ROC analysis, in the 92 normal subjects from the previous study, and 48 patients with known coronary artery disease. Sensitivity and specificity was then studied in a prospective study of 149 unselected patients referred for chest pain, with coronary angiography (>50% stenosis) as reference. This group included 59 normal, 36 (24%) patients with single vessel, 27 (18%) with double vessel and 27 (18%) with triple vessel disease.


Peak systolic velocity at peak stress, rather than change in velocity from baseline was the best discriminator of disease, but sensitivity was only 63% - 69% and specificity 60 – 67% for the different vascular regions, which is somewhat lower values than reported by the Brisbane group, and with cut of values of 10 - 12 cm/s in the basal segments. However, when a regression model including age, gender and peak heart rate was applied, sensitivity increased to 80 – 93% and specificity to 80 – 82%. These results imply that not only heart rate, but also age and gender should be taken into account when interpreting stress echo by tissue Doppler.

The differences in cut off values between the two studies can in part be explained by the fact that segmental velocities in Brisbane were measured in mid segment, in MYDISE in the base of the segment. As velocities increase from the apex to the base, this means that normal segmental velocities (and hence, cut off values) will  be higher in the MYDISE study. The difference in sensitivity in the two studies for peak velocity alone, may in part be explained by the number of segments analysed. IN the MYDISE study, only 7 segments were analysed, and it seems that positivity is defined by segmental velocities being reduced only in the specific vascular areas ((LAD: BA and MS; Cx: BL and BP; RCA: BI, MI and BS). If so, the sensitivity may be sub substantially
reduced. Frame rates are not reported in either study, but tended to be somewhat lower than what is customary at present (especially in the MYDISE study), this might result in some under sampling, so the cut off values might be higher with higher frame rate. So far no studies has addressed the timing of  motion by tissue velocities as an additional variable. peak velocities does not include the asynchrony induced by the delayed onset and post systolic shortening that is a marker of ischemia. Just looking at the timing of peak velocities if there is a suspicion of asynchrony will often answer this as illustrated below.

Even though peak velocities show comparable accuracy as wall motion score, at least for detection of ischemia, tethering makes the true location of ischemia difficult. That may be part of the problem of the MYDISE sty as well, analysing only typical segments and considering them positive only for stenoses in the vessels of the vascular territories considered.

It has previously been shown that the segmental specificity of velocities is low (40). Thus, reducing the number of segments necessary for a positive test, will reduce the specificity. Basically, using velocities in stress echo should be considered a screening for an ischemic response. The actual location of the ischemic areas should hypothetically be shown better in strain rate and strain.

Presence of PSS may give asynchrony between walls, where almost all of the wall may be out of phase, even if there are gradients of ischemia as shown below.



Stress echocardiography with development of ischemia in the inferolateral wall. At peak stress, the whole of the wall can be seen to move paradoxically, moving inwards (and towards the apex) after end of septal contraction.  Again, in a clinical situation, the interpretation can be facilitated by stopping and scrolling. The velocity (motion) confirms the visual impression, the whole inferolateral wall moves downwards in systole, and upwards after end systole (Yellow and green curves), while the septum shows normal apically directed velocities giving a total asynchrony between the two walls. This asynchrony is also evident by the curved M-mode, starting a the inferior base, going through the apex and ending at the septal base.This might be due to both apical and basal ischemia.


The strain curves below, separates the effects of the segments, showing systolic dyskinesia (lengthening)  with some net post systolic shortening in addition to the recoil in the base (yellow curve), and systolic hypokinesia in the apical segment (green curve) with post systolic shortening, compared to a fairly normal strain curve in the septum. Thus, deformation imaging showing most severe ischemic reaction in the basal part, giving highest probability of a Cx ischemia, which was confirmed angiographically.
In this case, the tissue velocities are sufficient to detect the presence of ischemia, but the deformation imaging shows the location and extent of the ischemia, while velocities shows asynchrony of the whole inferolateral wall.

Strain rate imaging

Feasibility of strain rate imaging was addressed in a study by Davidaviticus et al (111). They found that 95 % of segments were analysable during dobutamine stress. Due to noise problems strain rate imaging was not feasible during treadmill or bicycle stress. The study, however, was small and was limited to healthy individuals. The normal response during dobutamine stress was an increase in velocity, strain rate and strain at low dose dobutamine, a further increase in velocity and strain rate at high dose, when strain showed a plateau. This is intuitive, concordant with an initial increase in contractility and stroke volume at low dose dobutamine, giving increased stroke volume, but with increased heart rate without increased venous return at higher dobutamine levels resulting in a plateau or even diminished stroke volume. Velocity/SR of contraction, however, continues to increase as ejection time shortens. This in opposition to exercise, where increased venous return increases stroke volume even at high heart rate.Kowalski et al (112) extended the testing of SRI to patients with coronary artery disease, 20 patients with chest pain, 16 with positive coronary angiography were examined. Feasibility was over 95% of segments. Both narrow angle and wide angle sector gave similar results. Peak systolic strain rate showed a linear increase from baseline to peak. Ischemic segments (critical stenoses) showed no increase in strain nor strain rate during low and high dose dobutamine.However, they found that some ischemic segments showed normal velocity responses to dobutamine, and suggest that this is due to tethering.  A different explanation can be that isovolumic contraction velocities are mistaken for peak velocity during ejection, as shown in this clinical example. No overall analysis was done for the diagnostic criteria of ischemia out over clinical examples.Their study confirms that SRI may have a clinical potential, but was not designed to determine the ability of SRI to diagnose coronary artery disease.

The clinical value of SRI was addressed in a study by Voigt et al (113). The study included 44 patients and single photon emission computed tomography (SPECT) was used as reference method for ischemia, but with coronary angiography as well. The study reports 100% sensitivity and specificity of  SPECT compared with coronary angiography, somewhat higher than usual, indicating that this material is somewhat selected. Then SPECT is used as the gold standard for ischemia. In general, the sensitivity of SPECT against coronary angiography is around 90%. It can easily be argued that angio does not show ischemia, thus SPECT is a better reference. But that assumes a perfect sensitivity of SPECT. It can easily well be argued that bot SPECT and stress echo has limited sensitivity, and in that case, not all studies will show ischemia by both methods, and coronary angiography will then serve as an external reference that is the same for both methods.

In this study the feasibility was 92% for tissue velocities, and 85% for SRI, which is reasonable in our experience with SRI artefacts.

In non ischemic segments, peak systolic strain rate increased significantly with dobutamine stress, from -1.6 ± 0.6s-1 to 3.4 ± 1.4s-1, while strain during ejection time changed only minimally 17 ± 6% to 16 ± 9%. During dobutamine, 47 myocardial segments in 19 patients developed scintigraphy-proven ischemia. Strain-rate
increase from 1.6 ± 0.8s-1 to 2.1 ± 1.1s-1and strain decreased from 16 ± 7% to 10 ± 8%, both significantly different from non ischemic segments. Post systolic shortening (PSS) was found in all ischemic segments. By ROC analysis, the AUC was 0.57 for peak strain (not surprising as this includes post systolic strain), 0.65 for end systolic strain, 0.74 for peak systolic strain rate, 0.8 for time to end of negative strain rate and 0.9 for the ratio of  post systolic index (PSI). The PSI thus seemed to be the best parameter to identify stress-induced ischemia, however, as no confidence intervals are given, the significance of the differences cannot be ascertained. Furthermore, in qualitative analysis  of parametric strain rate imaging, compared with conventional grey scale readings SRI curved M-mode improved sensitivity/specificity from 81/82% to 86/89%. The statistical significance of this difference, however, is not given in the paper.
 





Colour SRI M-modes from septum of the same examination, showing clearly at 20 µg/kg/min the development of a prolonged shortening period in the apex,  but still systolic shortening as well. During peak stress, there is virtually no systolic shortening, only post systolic.
Strain curves at 20 µg/kg/min (top) and peak stress (bottom), showing systolic hypokinesia at low dose with PSS and akinesia in septum / dyskinesia laterally with PSS.

In a further paper from the same study (114), giving pretty much the same data, SRI is also compared to tissue velocities and displacement for diagnostic accuracy. Visual wall motion had a sensitivity/specificity of  81/82%, post systolic strain /peak strain had a sensitivity of 81/82% and segmental tissue velocities 74/63%. These numbers, however, refers to sensitivity against SPECT. One might theoretically apply this to a sensitivity of 90%, and end up with a traditional sensitivity of WMS against angiography of  73%, which is definitely lower than in other studies using harmonic imaging (104, 105). Again an instance of new methods leading to a decrease in sensitivity of established methods.

This might be due to several reasons:
The grey scale images are taken with Tissue Doppler data in the background, thus reducing the image quality and frame rate slightly. Recordings may to a certain degree be less optimised for endocardial visibility, as proper alignment are more important for tissue Doppler. Patients are included with less regard to good grey scale image quality as one expects to rely on both grey scale and tissue Doppler information. This, however, will make stress echo available to more patients, but as the general grey scale sensitivity may be expected decline, on has to utilise both 2D and tissue Doppler information.

This is analogous to the effect seen with harmonic imaging, and a parallel effect is described when using contrast stress echo for left ventricular opacification (123), although that study does not give the number of substandard recordings without contrast, nor the impact on sensitivity.

The velocity accuracy in detecting ischemia alone is comparable with the MYDISE study (110). This again illustrates the main principle, as segment velocities are dependent on overall function and adjacent segments, they are not suited to segmental analysis (40). If one only analyses the velocities in the ischemic segments, the sensitivity will be low as well. The overall sensitivity of peak velocity in any segment for presence of ischemia is not given. However, by the same principle, the overall sensitivity in detecting ischemia anywhere is good, if all segments are analysed, as shown by the Brisbane group. I  Thus, peak velocities is a fair screening for ischemia. On the other hand, for locating the area of ischemia, the strain rate indices is probably best.


A larger, cooperative study of dobutamine stress from Trondheim and Brisbane (128), including 197 patients, where half were used for ROC analysis, the other half to test the sensitivity and specificity of findings, showed that the feasibility of analysis was 65 - 85% of segments at peak stress, depending on method, but significantly lower than WMS by B-mode, which was 98%. Another study (132) showed a feasibility of 92% of segments at peak stress. However, this may reflect a too low rejection rate for reliable results as discussed elsewhere. Still, analysis was feasible in all patients. The results showed higher sensitivity with SRI, both by velocity gradient and segmental strain by combined ST-TDI, (87 and 84% for peak systolic strain rate and 87 and 88% for strain) versus WMS (75%). The significance of this was 0.02 - 0.04) There was a trend towards better specificity and accuracy of strain rate and strain compared to WMS, as well, but this was not significant.The post systolic index, however, was significantly poorer than strain and strain rate, (p 0.01 - 0.04), and with sensitivity of 71% probably no better than WMS.

Also, a larger prospective study from Brisbane (133), including 646 patients with an average follow up time of 5.2 years, prediction of all cause mortality was analysed in terms of clinical variables (diabetes mellitus, age, previous MI), resting and stress wall motion abnormalities and stress strain rate and strain. Peak wall motion score index, mean SR(s), segmental S(es), and segmental SR(s) were all predictors of mortality, but only segmental SR(s) (hazard ratio, 3.6; 95% CI, 1.7 to 7.2) was independently predictive. In sequential Cox models, the model based on clinical data (overall chi2, 12.7) was improved by peak wall motion score index (18.4, P=0.002) and further increased by either mean SR(s) (25.7, P=0.009) or segmental SR(s) (31.8, P<0.001).
It has been suggested that this may be that the mean value identified patients with regional ischemia who did not have the capacity of compensating with hyperkinesia in other segments. In that case this may be the incremental information, that is not derived by WMS. Peak systolic strain rate again had better predictive value than strain.

The sensitivity of 3 strain rate imaging parameters during peak stress; Peak syst. strain rate, end syst. strain and post systolic index PSI. Values for the segmental strain method and the velocity gradient method. sensitivity by PSI was significantly less, but only by the velocity gradient method.  From (128)
 Sensitivity of wall motion score (WMS) versus peak systolic strain rate and end systolic strain by both segmental strain and velocity gradient. Difference between either strain method and WMS  was significant. From (128) Incremental value of SRI variables in a series of Cox regression models predicting all-cause mortality. The clinical variables (diabetes mellitus, age, previous MI) were entered together (1), followed by separate models by combination of these with either resting WMSI (2) or stress WMSI (3). Then, clinical variables plus stress WMSI were entered together, and each SRI variable added in separate analyses: 4: segmental end-systolic strain, 5: mean peak systolic strain rate and 6: segmental peak systolic strain rate. From (133)

Thus there is reason to accept these results as evidence of independent value of strain rate imaging.

The clinical evidence is about dobutamine stress only. Early experience (111) seem to indicate that it is less feasible during exercise stress due to increase in motion artefacts, although this evidence is limited.

Still, Strain rate has a lot of pitfalls, and they tend to become even more exaggerated with increasing stress. A critical eye should always be applied to data quality before analysis, and all segments with low data quality should be discarded. The parametric imaging, is probably superior to visualise the extent of ischemia (and indeed to see if the curves are credible at all by having a certain extent), as well as for timing, especially tardykinesia. Only one stress echo study so far (113) has addressed the qualitative visual assessment of colour SRI.

Finally, as with all echo measurements, SRI should always be considered a part of the total echo examination.

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Editor: Asbjørn Støylen Contact address: asbjorn.stoylen@ntnu.no, Updated: 2011