Doppler echocardiography and tissue Doppler imaging in the healthy rabbit: differences of cardiac function during awake and anaesthetised examination.
ABSTRACT In the past years, Doppler echocardiography has evolved into a commonly used technique. More recent sophisticated advances in imaging quality have substantially improved spatial and temporal resolution allowing the adaptation of this technique to small animal models, particularly in rabbits but even in mice. Recently, parameters obtained by Tissue Doppler Imaging (TDI) have been shown to be more independent of pre- and afterload than classic hemodynamic Doppler measurements. Exploration of animal models may require anaesthesia but there is only very little information on the effect of anaesthesia on echocardiographic parameters in rabbits.
We therefore performed Doppler-echocardiographic examinations of 20 wild-type New Zealand White rabbits in awake state and under light ketamine-xylazine anaesthesia. Special focus was put on the evaluation of global and regional left ventricular systolic and diastolic function using TDI and the myocardial performance index (Tei-index).
Doppler-echocardiographic measurements including TDI in rabbits were feasible to assess cardiac morphology and function within a short examination time. There were some distinct changes of functional parameters during anaesthesia. Exemplary for systolic function, fractional shortening, cardiac output and systolic TDI velocity of the lateral wall decreased distinctly. Global left ventricular function measured by the Tei-index deteriorated.
Doppler echocardiography and TDI can be performed easily, quickly and safely in the rabbit. Anaesthesia with the cardiodepressive ketamine-xylazine shows some distinct Doppler-echocardiographically measurable negative effects on cardiac function. Thus, echocardiography with less cardiodepressive anaesthetic regimes or even without anaesthesia after training of the animals should be considered as alternatives whenever possible.
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ABSTRACT: This experimental study was aimed at evaluating the type of cardiac and pulmonary involvement, in relation to changes of the thoracic spine and cage in prepubertal rabbits with nondeformed spine following dorsal arthrodesis. The hypothesis was that T1-T12 arthrodesis modified thoracic dimensions, but would not modify cardiopulmonary function once skeletal maturity was reached. The study was conducted in 16 female New Zealand White (NZW) rabbits. Nine rabbits were subjected to T1-T12 dorsal arthrodesis while seven were sham-operated. Echocardiographic images were obtained at 12 months after surgery and parameters for 2-dimensional and M-mode echocardiographic variables were assessed. One week before echocardiographic examination, blood samples were withdrawn from the animals' central artery of the left ear to obtain blood gas values. One week after echocardiographic assessment, a thoracic CT scan was performed under general anesthesia. Chest depth (CD) and width (CW), thoracic kyphosis (ThK) and sternal length (StL) were measured; thoracic index (ThI), expressed as CD/CW ratio. All subjects were euthanized after the CT scan. Heart and lungs were subsequently removed to measure weight and volume. The values for 2-dimensional and M-mode echocardiographic variables were found to be uniformly and significantly higher, compared to those reported in anesthetized rabbits. CD, ThK, and StL were considerably lower in operated rabbits, as compared to the ones that were sham-operated. Similarly, the ThI was lower in operated rabbits than in sham-operated ones. Irregularities in thoracic cage growth resulting from thoracic spine arthrodesis did not alter blood and echocardiographic parameters in NZW rabbits.Indian Journal of Orthopaedics 03/2014; 48(2):184-92. · 0.62 Impact Factor
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ABSTRACT: Objectives The aim of the study was to report normal two-dimensional, M-mode, and Doppler echocardiographic findings from a large cohort of healthy, manually restrained, adult pet rabbits. Animals and Methods Forty healthy pet rabbits [22 Dwarf Lops (DL), 14 French Lops (FL) and 4 Alaskan (AL)] underwent a full physical examination and conscious two-dimensional, M-mode, and Doppler echocardiography. Results The median age of the rabbits was 21.5 months, the median weight was 2.9 kg (DL: 2.4 kg, AL: 4.35 kg, FL: 6.0 kg). Echocardiography with ECG monitoring was feasible in all rabbits. Left atrial and ventricular dimensions were significantly larger in FL as compared to DL; overall, a positive correlation with weight was present. No significant differences between breeds were identified for flow velocities. Trace regurgitation was detected at the aortic valve in 7/40 (17.5%) rabbits, at the tricuspid valve in 5/40 (12.5%) and at the pulmonic valve in 1/40 (2.5%) rabbits. Mitral inflow E and A waves were summated in 60% of cases. Conclusions The results of this study can be used as echocardiographic values in FL and DL for comparison with clinical cases, and may also be applicable for other breeds of similar sizes. Breed specific values should be used when measuring left atrial and ventricular sizes. However, no breed or size differences were found for the rest of the echocardiographic parameters, which may therefore be applicable for the general pet rabbit population.Journal of Veterinary Cardiology 06/2014;
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ABSTRACT: This paper reports radial colour and longitudinal mitral annulus pulsed-wave tissue Doppler findings in a large cohort of healthy, adult pet rabbits. Thirty-nine rabbits (22 Dwarf Lops, 14 French Lops and 3 Alaskan) underwent conscious echocardiography. The median age of the rabbits was 22 months and the median weight was 2.8 kg (Dwarf Lop 2.4kg/French Lop 6.0kg). Adequate radial colour and longitudinal pulsed-wave tissue Doppler traces were obtained in 100% and 85% of cases, respectively. Most systolic tissue Doppler parameters were significantly higher in French Lops than in Dwarf Lops. Separation of mitral inflow diastolic waves was present in 40% of cases using conventional spectral Doppler and in > 60% of cases using pulsed-wave tissue Doppler which could be beneficial when evaluating diastolic function in rabbits. This study can be used as a reference for normal echocardiographic tissue Doppler values for adult rabbits undergoing conscious echocardiography in clinical practice.Research in Veterinary Science 10/2014; · 1.51 Impact Factor
Doppler echocardiography and Tissue Doppler Imaging in the
healthy rabbit: Differences of cardiac function during awake and
Jörg Stypmanna,b,⁎,1, Markus A. Engelena,c,1, Anne-Kristin Breithardtd,2,3, Peter Milberga,
Markus Rothenburgere, Ole A. Breithardtf, Günter Breithardta,b, Lars Eckardta,b,
Poulsen Nautrup Cordulac
aDepartment of Cardiology and Angiology, University Hospital Münster, Germany
bInterdisciplinary Center for Clinical Research, Central Project Group (ZPG 4a), Westfälische Wilhelms Universität, Münster, Germany
cUniversity Medical Center Utrecht, Department of Medical Physiology, The Netherlands
dVeterinary Anatomy I, Ludwig-Maximilian-University, München, Germany
eDepartment of Thoracic and Cardiovascular Surgery, University Hospital Münster, Germany
fDepartment of Cardiology, University Hospital Mannheim, Germany
Received 19 October 2005; received in revised form 7 January 2006; accepted 11 March 2006
Available online 27 June 2006
Objective: In the past years, Doppler echocardiography has evolved into a commonly used technique. More recent sophisticated advances in
imaging quality have substantially improved spatial and temporal resolution allowing the adaptation of this technique to small animal models,
particularly in rabbits but even in mice. Recently, parameters obtained by Tissue Doppler Imaging (TDI) have been shown to be more
independent of pre- and afterload than classic hemodynamic Doppler measurements. Exploration of animal models may require anaesthesia
but there is only very little information on the effect of anaesthesia on echocardiographic parameters in rabbits.
Methods: We therefore performed Doppler-echocardiographic examinations of 20 wild-type New Zealand White rabbits in awake state and
under light ketamine–xylazine anaesthesia. Special focus was put on the evaluation of global and regional left ventricular systolic and
diastolic function using TDI and the myocardial performance index (Tei-index).
Results: Doppler-echocardiographic measurements including TDI in rabbits were feasible to assess cardiac morphology and function within a
short examination time. There were some distinct changes of functional parameters during anaesthesia. Exemplary for systolic function,
fractional shortening, cardiac output and systolic TDI velocity of the lateral wall decreased distinctly. Global left ventricular function
measured by the Tei-index deteriorated.
Conclusions: Doppler echocardiography and TDI can be performed easily, quickly and safely in the rabbit. Anaesthesia with the
cardiodepressive ketamine–xylazine shows some distinct Doppler-echocardiographically measurable negative effects on cardiac function.
Thus, echocardiography with less cardiodepressive anaesthetic regimes or even without anaesthesia after training of the animals should be
considered as alternatives whenever possible.
© 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Echocardiography; Tissue Doppler Imaging; Rabbit; Anaesthesia; Awake; Narcosis
International Journal of Cardiology 115 (2007) 164–170
⁎Corresponding author. Universitätsklinikum Münster Medizinische Klinik und Poliklink C Kardiologie und Angiologie Albert-Schweitzer-Str. 33 D - 48149
Münster, Germany. Tel.: +49 251 8347617; fax: +49 251 8347684.
E-mail address: Stypmann@mednet.uni-muenster.de (J. Stypmann).
1These authors contributed equally.
2These data are part of the doctoral thesis of A.-K. Breithardt.
3Current address: Von-Esmarch-Str. 117, 48149 Münster, Germany.
0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
Recent developments in animal models of cardiovascular
diseases have made them an increasingly important tool in
cardiovascular research. Rabbit models have vastly been
used, especially in the study of arrhythmogenesis as
arrhythmias in relatively large rabbit hearts are more
comparable to human arrhythmias, particularly due to more
“critical mass” for reentry as compared to smaller animal
models like mice. Doppler echocardiography has evolved
into a commonly used technique in various animal models
due to recent advances in the imaging processes that have
improved spatial and temporal resolution. This as well as
miniaturization has led to the adaptation of this technique to
the study of the physiology of animal models that now
reliably allow the non-invasive assessment of cardiovascular
morphology and function.
Anaesthesia may have a profound effect on cardiac
function, but there is only scarce information on its effect on
cardiac function in the rabbit. Although Doppler echocardi-
ography is widely used, only scarce echo data on rabbit
models are available. Tissue Doppler Imaging has the
advantage to be rather independent of preload . We,
therefore, systematically performed Doppler echocardiogra-
phy including M-Mode, 2D and TDI in 20 wild-type New
Zealand White rabbits of either sex in the awake state as well
as during anaesthesia to obtain normal values and to evaluate
the effect of anaesthesia on cardiac function.
Animal experimental procedures were performed in
accordance with institutional guidelines and approved by
local authorities. The investigation conforms to the Guide for
the Care and Use of Laboratory Animals published by the
US National Institutes of Health (NIH Publication No. 85-
23, revised 1996). We studied twenty 16-week-old wild-type
New Zealand White rabbits (10 male, 10 female, Peter Rolli,
Oelde, Germany). They were housed in the Central Animal
Facility of the Medical Faculty of the University of Münster
at 20 °C at 60% humidity with a 12:12-h light–dark cycle
and fed with a standard diet and water ad libidum.
Doppler echocardiography was performed in awake
animals and under light ketamine–xylazine anaesthesia in
each animal. The thoracic fur was completely removed and a
1-lead ECG was obtained during all measurements to
monitor heart rate continuously.
For the awake examination, animals were held on the lap
of the examiner (A.K.B.) and first allowed to adapt to this
situation for 5 min. This situation was trained with the
animals several times before the examination to train them
and to avoid too much stress. Echocardiography was
performed in a sitting position.
For the examination in light anaesthesia, animals were
anesthetized by intramuscular injection of a mixture of
ketamine (50 mg/kg) und xylazine (4 mg/kg) and allowed to
breathe spontaneously. The anesthetized animals were
placed in a left lateral position on a custom-built echo-
table on a feedback-controlled heating pad to maintain body
temperature at 37 °C.
Transthoracic Doppler echocardiography was performed
using a commercially available digital cardiac ultrasound
platform equipped with a 12-MHz short focal-length phased
array transducer (SONOS 5500, B2 software package,
Philips Medical Systems, The Netherlands). A smooth layer
of ultrasound gel previously centrifuged at 3000 rpm for
10 min to avoid air bubbles that would disturb acoustical
coupling was placed on the chest of the rabbits. The probe
was gently dipped into this layer of gel avoiding any pressure
on the thorax.
Short axis and apical four- and five-chamber views in the
long axis were obtained to measure the length of the left
ventricle in end-diastole and diameters of the LV outflow
tract, aortic root and left atrium. B-mode guided M-mode
echocardiography was performed in theparasternal long-axis
view at the mid level of the papillary muscles. End-diastolic
and end-systolic dimensions of the LV-cavity as well as
anterior and posterior wall thickness were assessed accord-
ing to the leading-edge method of the American Society of
The percentage of fractional shortening was calculated as
ð Þ ¼
LVEDD ? LVESD
For determination of systolic outflow of the left ventricle,
pulsed wave Doppler signals were obtained by placing the
sample volume parallel to the flow in the long-axis 5-
chamber view into the left ventricular outflow tract. Mitral
inflow was assessed in the apical 4-chamber view with the
sample volume placed at the level of the mitral leaflet tips.
Monoplane left ventricular ejection fraction (EF) was
calculated from the apical 4-chamber view using the method
of discs (modified Simpson rule) [3,4]. In addition, EF was
measured using the automatic-border-detection (ABD)
function of the ultrasound platform .
Left ventricular stroke volume (SV) was calculated as
SV ¼ p ? ðLVOT=2Þ2? VTI
π=3.14, VTI = velocity time integral of the aortic flow.
Cardiac output (CO) was calculated as
CO ¼ SV ? HR
SV = stroke volume, HR = heart rate
Isovolumetric relaxation time (IVRT) was measured as
the time interval between end of aortic outflow and onset of
the mitral inflow by PW-Doppler. Isovolumetric contraction
165J. Stypmann et al. / International Journal of Cardiology 115 (2007) 164–170
time (IVCT) was measured as the time interval between the
end of mitral inflow and onset of aortic outflow by PW-
Doppler (Fig. 1).
The myocardial performance index according to Tei [6–
9] (Tei Index) was calculated as
MPIðTeiÞ¼IVCT þ IVRT
with IVCT=isovolumetric contraction time, IVRT=isovo-
lumetric relaxation time, LVET=left ventricular ejection
Tissue Doppler imaging was performed from the apical 4-
chamber view as previously described [10–12]. In brief, the
sample volume was placed at the septal and lateral insertion
site of the mitral annulus. Gain and filter settings were
adjusted to eliminate background noise and allow for
recording of clear tissue signals. Measurements included
early and late diastolic as well as systolic maximal velocity.
2.2. Statistical analysis
For each Doppler-echocardiographic parameter, the mean
of at least three beats was calculated. All results are given as
means±standard deviation. Statistical analysis was per-
formed using SPSS software (Version 13, SPSS, Chicago).
Whenever appropriate, the data of the awake and the
anesthetized animals were compared with Student's t-test
for matched pairs. Two-sided P-values<0.05 were consid-
ered as significant.
Technically adequate measurements could be obtained
in all 20 animals. No rabbit died during or after
examination. Mean body weight was 2.92 kg (range
2.45–3.35 kg). Weight did not change significantly
between the examination under narcosis and in the awake
state. As expected, heart rate was significantly lower in the
anesthetized (198±37 bpm) as compared to the awake
animals (234±26 bpm, p<0.0001). Heart rate was stable
during the whole examination as well in the awake state as
under anaesthesia. All echocardiographic studies were
completed within 20 min. Representative examples are
shown in Fig. 2.
Results of the B- and M-mode measurements are shown
in Table 1. Fractional shortening was 17.4% lower during
anaesthesia as compared to the awake state ( p=0.001),
mainly due to an increase of the LVinner diameter in systole
Doppler measurements including TDI and calculated
indices are shown in Table 2. Several significant differences
are found between the awake and anaesthetised state.
Exemplary for systolic function, cardiac output (−27%,
p=0.006) and systolic TDI velocity of the lateral wall
decreased distinctly (−23%, p=0.038). Global left ventric-
ular function measured by Tei index deteriorated (0.57±0.20
versus 0.71±0.16, p=0.011). In some animals (3 of 20), E/A
ratio was reversed under anaesthesia. There was a significant
underestimation of ejection fraction using automatic border
detection compared to the EF determined according to
Fig. 1. Measurement of IVCT, IVRT and calculation of myocardial performance index according to Tei .
166J. Stypmann et al. / International Journal of Cardiology 115 (2007) 164–170
Simpson's rule (for examination of awake animals–11%,
p=0.0042 and for animals during anaesthesia–17%,
Doppler echocardiography of animal models more and
more evolved to be an important non-invasive tool in
fundamental and clinical cardiovascular research. A
complete Doppler-echocardiographic examination includ-
ing TDI can be obtained in the awake as well as in the
anaesthetised rabbit. Examination in the awake state leads
to more physiological results as compared to echocardi-
ography in ketamine–xylazine anaesthesia whereas exam-
ination in the awake status is more difficult, more time-
consuming, and needs special training of the animals so
that they are accustomed to the examination situation and
of the examiner to perform the examination carefully and
Fig. 2. Representative echocardiographic examples. White bars represents 200 ms. PW–Doppler of the aortic outflow (awake A, narcosis B), mitral LV inflow
(awake C, narcosis D with reversal of the E/A ratio), M–Mode of the LV (E) and aorta+LA (F), TDI (awake G, narcosis H with reversal of the E/A ratio).
B- and M-mode measurements
LVOT=LV outflow tract; LVAWd=LV anterior wall in diastole;
LVPWd=LV posterior wall in diastole; LVIDd/LVIDs=LV inner diameter
in diastole/systole; FS=fractional shortening; ns=not significant.
167J. Stypmann et al. / International Journal of Cardiology 115 (2007) 164–170
Heart rate under anaesthesia was significantly lower as
compared to heart rate in the awake state. The higher heart
rate in the awake animal is mainly due to the increase of
sympathetic tone which is counteracted by a negative
inotropic effect of the anaesthetics and a well-known
negative chronotropic effect particularly of xylazine [13–
15]. Marano et al.  reported the physiologic heart rate of
the New Zealand White rabbit measured by telemetry
without any restrainment or drug-effects to be 218±4 bpm,
suggesting that the higher rate in our animals in the awake
state was indeed due to an increase in sympathetic tone and
the lower rate during anaesthesia was mainly due to a direct
negative chronotropic effect of xylazine. Different sympa-
thetic tones should be taken into account when assessing
cardiac function of rabbits under awake or anaesthetized
To the best of our knowledge, there has been no
international publication showing echocardiographic data
in the awake rabbit. We did not find any difference in
structural measurements between animals in the awake state
and under anaesthesia. However, most functional parameters
in M-mode and pulsed-wave Doppler measurements were
changed under anaesthesia as compared to the awake state.
Particularly, fractional shortening and cardiac output as
measurement for systolic function decreased significantly
under narcosis. This can be explained by a direct negative
inotropic and chronotropic effect of the anaesthetic regime
used in this study and by reduction in sympathetic drive
[14,15,17,18]. There was no significant change in E/A-ratio
since the maximum velocity of E- and A-wave decreased to a
similar degree. But there was a reversal of the E/A-ratio in
some animals under anaesthesia, showing anaesthesia-
induced impairment of LV diastolic function . The
highly significant decrease of cardiac output during
anaesthesia can largely be explained by the significant
reduction of heart rate as stroke volume only decreased
slightly without reaching statistical significance. LVejection
fraction according to Simpson's rule did not show any
difference comparing the examinations of awake rabbits with
the examinations under narcosis whereas there was a
significant underestimation of EF determined by automatic
border detection comparing the different methods of
determination. This is probably due to problems inherent
in the software algorhythmus of this method, mainly
inaccurate detection of the endocardial border in the small
and fast-beating rabbit heart. Use of automatic border
detection is also discussed quite controversially in human
patients . In the future, these problems might be
overcome by the use of contrast echocardiography for better
delineation of the left ventricular cavum and by three-
dimensional echocardiography to resolve the necessity of
presuming a symmetric left cavity for the calculation of left
There are only scarce data on echocardiography in rabbits
in the literature, especially on TDI. Anaesthesia leads to a
significant increase in LV ejection time and isovolumetric
contraction time whereas isovolumetric relaxation time
tended to increase but this trend did not reach statistical
significance. This resulted in a significant increase of the
myocardial performance index (Tei index), indicating a
significant global impairment of systolic and diastolic
function under anaesthesia [6–9]. To the best of our
knowledge, no previous study has used the myocardial
performance index as a measure for global systolic and
diastolic LV-function in the rabbit.
We found distinctly lower wall motion velocities as
compared to the scarce data in the literature [10–12]. This is
Doppler-echocardiographic measurements including TDI and calculated
EF (%) (Simpson)
EF (%) (ABD)
E-wave max (cm/s)
A-wave max (cm/s)
TDI syst LW (cm/s)
TDI E LW (cm/s)
TDI A LW (cm/s)
TDI syst septal (cm/s)
TDI E septal (cm/s)
TDI A septal (cm/s)
Ao Vmax=maximum flow velocity aorta; LET=LV ejection time;
SV=stroke volume; EF=ejection fraction; CO=cardiac output; E-wave
max=maximum early flow velocity mitralis; A-wave max=maximum late
(atrial) flow velocity mitralis; IVRT/IVCT=isovolumetric relaxation/
contraction time; MPI=myocardial performance index; TDI=Tissue
Doppler Imaging; ns=not significant.
Comparison of our values with literature
Heart rate (bpm)
42±6 / 62±6
37.9±9.4 26.5±6 41±8
min/max=minimal and maximal value found in the literature, further
abbreviations see Tables 1 and 2.
168J. Stypmann et al. / International Journal of Cardiology 115 (2007) 164–170
probably due to the use of different ultrasound-platforms and
different settings. We could show a significant decrease in
systolic wall motion velocity under anaesthesia representing
impairment of regional systolic LV-function. Furthermore,
there was a distinct increase of atrial contribution to LV
filling as compared to the awake state. This underlines the
problems of anaesthesia in rabbits.
Our measurements are comparable to those reported
previously (Table 3). However, we did not find any
information on LV ejection time, cardiac output, and
isovolumetric contraction in the surveyed literature.
One limitation of this study is the use of ketamine–
xylazine anaesthesia. But on the other hand, this anaesthesia
was chosen deliberately because of the well-known
cardiodepressive effects as one of the major issues of this
study was to prove if TDI and MPI could distinguish the
global and regional left ventricular performance under the
different examination settings. Most available anaesthetics
have a distinct impact on cardiac function, partly by their
influence on autonomic tone, partly due to a direct
cardiodepressive effect. Newer volatile anaesthetics like
isoflurane or sevoflurane have less impact on cardiac
function and heart rate but this kind of anaesthesia was not
yet readily available when we started our experiments. The
impact of these anaesthetics on ultrasound examinations
including TDI, strain and strain rate is the focus of
subsequent recent studies in our animal laboratory. Intrave-
nous/intramuscular injection narcosis, particularly keta-
mine–xylazine, is still very common in research as well as
in veterinarian practice. Comparison of echocardiography in
the awake state versus under anaesthesia was part of the
scope of this paper.
We did not validate our measurements directly to invasive
measurements but this was not in the primary scope of this
study. Comparisons between echocardiographic parameters
including TDI and invasive measurements have already been
done extensively in other studies, mainly in human patients
(e.g., [21,22]). Finally, invasive measurements in the awake
animal cannot be easily performed. Data on reproducibility
of echocardiographic examinations in rabbits were not
performed as the main scope of the presented study was to
prove the discriminative power of TDI and MPI to detect
changes in left ventricular function. Extensive experience of
our group in qualified repetitive echocardiography's in small
animals has been published before [23–26].
6. Conclusions and outlook
We could show that a complete Doppler-echocardio-
graphic examination of the rabbit is feasible within a short
examination time during light anaesthesia as well as in the
awake state. Since various anaesthetic agents may have a
distinct negative impact on cardiovascular function, the
choice whether animals are examined in the awake state or
under light anaesthesia should be reflected carefully.
Echocardiographic measurements in the absence of cardi-
odepressive effects of anaesthetic drugs allow obtaining
more physiological parameters. On the other hand,
examination without any anaesthesia is more cumbersomely
and a cardiovascular effect of a slight increase in
sympathetic tone cannot be ruled out. These problems
might in future be overcome by introduction of newer
anaesthetic regimes using volatile narcotics as isoflurane,
sevoflurane or Xenon.
Tissue Doppler Imaging and calculation of the Tei-index
should be implemented as part of standard rabbit echocar-
diography protocol to judge global and regional systolic and
diastolic LV-function in rabbit models. Thereby, rabbit
models of cardiovascular diseases can be examined more
independent of pre- and afterload. Thus, the reliability of
these measurements is improved and the results are better
transferable to clinical patients. In the future, TDI measure-
ments can be supplemented by the introduction of strain- and
This work was partly supported by grants from the
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