Normal values for
spectral tissue Doppler annular left and right
ventricular diastolic velocities by age and gender from
the HUNT study. From (165).
by sex and age. Values are mean (SD). pwTDI: Pulsed Tissue
Doppler recorded at the top of the spectrum with
minimum gain. Values of e' decline with age, a'
increase. Normal range is customary defined as mean ±
ventricle, mean of 4 walls
ventricle (free wall)
|< 40 years
|40 - 60 years
|> 60 years
|< 40 years
|40 - 60 years
|> 60 years
The study is based on 1266 healthy individuals from
the HUNT study by Dalen et al (165
age dependency of values is evident. Colour tissue Doppler
gives mean values, which are consistently lower than
pulsed wave values, as discussed here
E is pressure driven, but e' is not to the same degree,
the relaxation actually being the cause of the pressure
drop. However, this load independency is not absolute, as
This means that the ratio
of E/e' can be used for assessment of left atrial pressure
). If both E and e'
increases, the ratio remains unchanged, and the increase
in flow is due to higher relaxation rate. (For instance in
exercise in normals (29
However, if E increases without e' increasing
simultaneously , the increase in flow must be driven
by increased filling pressure instead of by
relaxation (as for instance in exercise in patients with
impaired relaxation reserve (160
), and the increase
in the E/e' ratio is related to the increase in filling
(atrial) pressure. However, if E remains
unchanged and e' decreases, it is not physiologically
meaningful to take the increased ratio as a measure of
increased filling pressure.
In fact, in
transition from supine to sitting the E/e' increases
while filling pressure decreases (160)
Thus the E/e' relates only to filling pressure when E
An E/e' < 8 is considered normal, while E/e' > 15 is
considered a sign of elevated LA pressure.
Normal values for left
ventricular E/e' from the HUNT study (From 165).
The E/e' ratio was age dependent, as has been shown
previously in a smaller study (166
and confirmed in the larger HUNT study:
Values are mean
(SD), and is the average of four walls. The E/e'
can be seen to increase with age.
|40 - 60
The age dependency of E/e' is evident. This is actually
one of the reasons for the "grey zone" between 8 and 15,
as normal range for the age group < 40 is below 8.2
(mean + 2SD), between 40 and 60 it would be < 9.9 and
above 60 years it would be below 13.4.
In a smaller sample of 100, cTDI was compared to pwTDI,
and the values by cTDI were 2.2 lower than pwTDI. The
ratio in the septum was 2.5 lower than in the lateral
wall, but very similar to the mean of four walls. It is
evident that by a normal range of mean ± 2SD, the normal
range in the youngest group is 3.0 - 8.2 and in the oldest
group 3.0 - 13.4. This explains previous findings of
the ambiguity of the interval from 8 - 15 concerning
relation to filling pressure. It should be age adjusted.
Where should measurements
of e' be done?
The differences between walls are even greater in early
diastolic than in systolic velocities. Thus, the e' and
hence, the E/e' is highly site dependent. This has been
shown several times, in the largest normal material being
the HUNT study (165
In the HUNT study the e' did show the following normal
values for pulsed Doppler per wall
Thanks to observant reading by Charlotte
Bjørk Ingul it was discovered that the
values given in the table blow were S' values, not e'
Now the correct values
are in accordance with the normal values given in the
) are given below
|e' (SD) cm/s
The general principles of the site specific variability,
however, still applies, and the E/e' values below were
correct from the start.
This means, of course, that the E/e' also varies with the
site of e' measurement:
E/e' from pwTDI according to age and site of e'
|Mean of four points
It is evident that there is considerable site
dependency of the E/e' as well. It is also evident that
there is little difference between mean of four points
versus two points, when only mean and SD are considered.
However, the Standard deviation is a large population
study reflects biological rather that measurement
variability. The study of Thorstensen et al (154
)did show an
improvement in reproducibility of about 15% of e'
measurement using the mean of septal and lateral, compared
to either of them alone, and a further
(p<0.001) using four-point compared to two point
Also, all systolic measurements of MAE
have been established from the start
as being the mean of four points, although two points seem
to work equally well in terms of mean, if not in terms of
reproducibility. Thus, in the interest of robustness and
to harmonise systolic and diastolic measures, the logical
thing would be to chose four point average for e' as well.
But logic has not got anything to do with it.
) in one of
the first observational studies used the lateral point. In
the early invasive validation studies; Nagueh (71
) and Sundereswaran (197
) used the
lateral wall alone, Sohn the septal point (70
) while Ommen
) studied both the
septum and the lateral point, as well as the mean. He
found the best correlation between E/e' and filling
pressure using the septum alone. Present
recommendations, however, favors mean of septal and
). It is
argued by some that the invasive validation work has been
done with one-site measurements, but at least, the HUNT
provides normal data for all sites.
dependency of diastolic tissue velocity (e')
However, the e' is not entirely load independent. As
normal subjects are sat upright on a bicycle (not using
their leg muscles, and thus reducing venous return), the
filling pressure drops, and so does e' (29
). The drop in
filling pressure is evident by decreased mitral flow E,
decreased LVEDV and increased HR (160
). This has also been
shown as e' changes after dialysis (178
) and in applying
lower body negative pressure (179
AS the relaxation rate
declines, and atrial pressure increases, however,
there will surely be a cross over point where the load
takes over as the main lengthening mechanism. In this
case the diagram above will no longer be valid, and
the e' relates to filling pressure more than
relaxation and elasticity. In this case the e' relates
to lenghthening load.
humpback whale in Wilhelmina Bay, Antarctica.
Load dependency of E/e'
As the e' is load dependent, even the E/e' may be be.
At low pressures, the e' actually changes more
than the E,
as LA pressure decreases, as has been shown
consistently by the supine to sitting transition (29
). This may be
due to the mechanism of load dependency being
different, and e' may be more
load dependent at low loads,
which could be explained by the diagram above.
Ischemic post systolic
shortening in diastole
As seen above
, ischemic post
systolic shortening will also affect diastolic filling:
|As seen here, the post
systolic shortening in the apex occurs
simultaneously with the elongation of the
normal base, where filling in principle should
|Looking at the colour
M-mode, we can e an intraventricular flow of
short duration, at end ejection. But as seen
here, in this case there is some early onset
of diastolic filling, which is cut short by
flow, thus the intraventricular filling is
delayed by the PSS.
|Mitral ring and flow
velocities from the case just aboveabove. In
this case, timing of the early filling was
fairly similar, despite PSS in the seoptum: Time
to onset of e' wave was 480ms in the septum, 477
in the lateral wall and 489 to mitral flow E.
Tme to peak e values were fairly similar too:
Septum 535, Lateral 541 and flow
563 ms. Thus in this case,
the inflow to LV is less affected, mitral flow
is slightly later than tissue velocities,
which is as expected. However intraventricular
flow can be seen to be hindered.
|This is the values from
the case shown previously.
In this case there is delayed onset and peak
of e' wave in the septum where there is PSS, compared
with lateral wall, and even earlier onset of E
wave in mitral flow, possibly indicating
elevated atrial pressure. In this case the
mitral E was 65 cm/s, septal e' was 6 cm/s
(E/e' 10.8) , lateral e' 9 cm/s (E/e' 7.2)
(giving a mean e' of 7.5, mean E/e' of 6.7).
Comparison of pulmonary venous flow and mitral
flow A waves, indicates increased end diastolic
In the case of ischemic PSS, however,
there may be imitations to the use of E/e' ratio in
estimating filling pressures, as they may not be
simultaneous, neither in onset nor peak.
It is evident that Ischemic PSS may interfere with filling
pressure. However, some authors have suggested that PSS is
actually the cause
of diastolic dysfunction. This
is really putting the cart before the horse, to say it
mildly. From the discussion above
is really the other way around, delayed relaxation in
ischemia that is the cause of ischemic PSS.
E and A fusion
In hemodynamic thinking, it is customary to start the
heart cycle with ejection, and the to proceed to diastolic
filling, hence S - E - A. This is the way tissue Doppler
is presented as well. However, each hart cycle start with
a sinus node activation, followed by an atrial activation
and atrial systole, and this is the customary way of
describing the ECG, hence P - QRS - T. But this
corresponds to the sequence of A - S - E, which may be a
help in describing the relation of E and A in relation to
heart rate as illustrated below.
cycles illustration the relation between E and A
with heart rate and PQ time. Cycle I to II show normal
PQ time and RR-interval from I to II, i.e. normal
heart rate, resulting in a normal diastasis period
between E of I and and A of II. Cycle II to
III shows higher shorter RR-interval, i.e. higher
heart rate. As heart rate is increased, it
means that P and hence A of cycle III , comes
earlier after cycle II. Thus, this explains why it
is the diastasis that is shortened with increasing
heart rate. Cycle III to IV, shows the same
RR-interval as I to II, i.e. same heart rate, but
with longer PQ time. Heart rate regulation
modulates the RR (or, actually PP) interval, but in
this case the PQ interval is prolonged in relation
to the RR interval. This has the same effect as
reduced RR interval; the PQ as fraction of RR
decreases, and the diastasis is abolished.
from a patient with 1st degree AV block, PQ time
of 272 ms at a HR of 73. There is partial
EA fusion at rest, showing up in mitral flow
(left), pw and colour tissue Doppler (middle and
it also changes the annulus motion pattern, as
the diastole moves more or less continuously.
Thus, as heart rate increases, it is the diastasis
that is shortened first, however, after the diastasis
interval is zero, the next step is fusion of the E and
A waves as shown below:
with increasing heart rate (or PQ time).
the numbers on this image are not related to the
numbers on the image above.) 1:
No fusion and discernible diastasis. 2:
Shortening of RR-interval first abolishes the
diastasis. 3: Further shortening of the
RR-interval leads to partial fusion of the E and
A wave and e' and a', respectively. the peak E
and e' is still separate, but the A and a' are
atrial velocities added to the remaining
velocities of the early phase, as shown by the
arrows in the upper diagram. In the velocity
curves, this is seen as the A/a' wave "climbs"
up (down) the descending limb of the E wave. 4:
At higher heart rate, the E and A are completely
fused, and the separate effect of ventricular
relaxation ant atrial contraction can no longer
Patient with Wenckebach block,
showing progressive E and A fusion as the
P-wave comes closer to previous
T-wave, until one beat is dropped.
Prolongation of PQ-interval reduces the Q-P
interval. Thus, the diastasis varies
inversely with PQ-time.
Although there is adaptive shortening
of both QT interval and PR interval, this does
not compensate for the shortened RR interval,
with fusion the diastolic period shortens more
with decreasing RR interval (29) and
ventricular diastolic filling period
(DFP) and ejection period (LVET) in
relation to heart rate during
exercise. Below HR 110, the RR
interval and DFP shortens in parallel,
showing the the diastasis is shortened
first, while ejection time shortens
much less. Above 110, there is
parallel shortening of LVET and DFP,
both contributing to the shortening of
RR interval. The study also showed
that the LVET and RR interval was only
linear below HR 100 (29).
|E and A with
increasing heart rate during an exercise
test in one patient. At HR 65,there is
separate E, a and diastasis, both in
mitral flow and in tissue Doppler as
evident by the fact that tissue velocity
is 0 between e' and a'. At HR 88 there
is partial fusion, neither E nor e'
reaches 0 before the start of A and a',
respectively, and the A and a' are
higher in absolute values due to
this. At HR 94 there is more
fusion, but the peak of the E and e' are
still discernible, and can be measured,
as a measure of ventricular
diastolic function. The E/A and e'/a'
ratios, however, are useless, as the A
and a' are summation velocities. The A
and a' are increased further. At HR 121,
the E/A and e'/a', respectively, are
nearly completely fused. The peak E and
e' can no longer be discerned. The peak
diastolic velocity is far higher (in
absolute values) that the E or e' and
cannot be compared.
fusion, peak E and e' ,
and thus the effect of ventricular relaxation
can still be seen and measured. However, peak
A and a' are now a sum of the velocities due
to atrial systole and the remaining velocities
due to ventricular relaxation. This means:
total fusion, the E and e'
velocities, and thus ventricular diastolic
function cannot be measured separately. The
diastolic function measured by the fused wave,
is the sum of ventricular relaxation and
atrial contraction velocities, and can still
be taken as a measure of
atrioventricular diastolic function. But
- The A and a' are higher
than when separate, and no longer a
measure of atrial function, and thus:
- The E/A ratio is no longer a
measure of the relative contribution of
the two mechanisms, and is nearly useless.
This point is important in three
diastolic function cannot be measured
- In an exercise or inotropic test
, when heart rate becomes high
enough, the fused wave cannot be compared
with the E wave at lower heart rates.
have higher heart rates, and partial fusion is
common at rest, and even total fusion in
degree AV-block may give fusion at
normal resting heart rates.
- In exercise
testing, the increasing heart
rate leads to total fusion, usually at HR
around 100. This means that for diastolic
dysfunction, exercise tests are not as useful
at HR > 100. In dysfunction due to ischemia
at higher heart rates, however, ischemic
stunning may persist for some time, while
heart rate falls, and may still be useful.
Some invasive studies, however, seem to indicate that
using the ratio between the fused EA wave and the fused
e'a' wave, the filling pressure can still be estimated (198
), as well as in
atrial fibrillation where the a wave is absent, and the E
and e' waves are higher (199
Left bundle branch block
Looking at the diastolic measures, there is some
evidence that the asynchrony in left
bundle branch block affects diastole as well: The
use of the E/e' ratio, relates tissue velocity to flow
velocity, assuming that the discrepancy should be an
expression of filling pressure. But that also
presupposes that the peaks are simultaneous, which they
are very often not, when there is LBBB. And in fact, if
the peaks are not simultaneous, the ratio has no
physical existence, and is not meaningful at all.
Comparison of septal mitral velocity and
mitral flow. As there is septal early flash, late
systolic stretch and post systolic recoil as
another section, the e' is delayed and the
E/e' is meaningless as a physical entity.
However, this may vary:
|Looking at the spectral
Doppler traces aligned by ECG (first vertical
line) there is post systolic motion (PSS)
in the septal trace, which corresponds to a
delayed e' wave. Laterally, there is no PSS,
but there is corresponding delay in the peak
e', the e' wave is seen slowly sloping towards
the peak. The mitral flow is slightly affected
as well, the peak E is similarly delayed. This
leads to a partial fusion
of E and A, as in 1st
degree AV-block, as the next P and Awave
comes early in relation to the delayed E wave.
Thus, there may be potential for developing
partial AV-block, despite normal PQ-time.
||In this case, however,
there is similar dely of the septal e' wave,
but the lateral peak e' is seen slightly
earlier, abd the E wave corresponding to the
lateral e'. It
seems evident that in this case, the septal
E/e' ratio is not strongly associated with
filling pressure, as they are not
||In this case, the septal
PSS is delaying the septal e' even more, but
again with no delay in the lateral e'. And the
mitral flow peak E is earlier than both. It
seeems evident that in this case, meither E/e'
ratio is not as strongly associated with
filling pressure, as they are not
simultaneous. And the fact that the
flow E is earlier than the tissue e',
might indicate that filling pressure actually
|Another case, but with
lower S'in the septum, indicating a poorer
septal function, again the e'
in the septum can be sen to be delayed, and later
that the mitral flow E, which in this case is
more synchronous with the lateral e'. It
is difficult to see that the E/e' ratio, at
least the septal one expresses filling
pressure, as the peaks are not simultaneous.
In this case, the E/e' was 17.5 for the septal
e', 7.7 for the lateral e' and 10.7
for the mean e' (however, the validity of
taking the mean of non simultaneous peaks is
dubious). As the lateral e' is simultneous
with peak E, this should be a better measure
of filling pressure????
However, in the last case, the Valsalva indicates an
elevated atrial pressure:
During Valsalva, the E/A ratio drops from 0.78
to 0.33 and the flow pattern becomes that of
typical delayed relaxation.
Limitations of the E/e'
As the investigantions have continued, there has been
shown severe limitations of the E/e' in estimating atrial
The most evident is explained above, where there is total
E/A (and e'/a') fusion, the combined e'/a' wave do no
longer measure the relaxation alone, but the combination
of ventricular relaxation and atrial systole. Also the E/A
wave do relate to atrial pressure, but no longer the mean
pressure but the peak pressure during atrial systole,
which may differ.
AS we have shown earlier, the E/e' increases in the
sitting position, while filling pressure drops. Thus the
studies are mainly valid for supine acquisitions.
High filling pressures:
If the filling pressures are high, the filling pressure
(lengthening load) may take over as the main mechanism for
the early motion of the mitral ring, as discussed above
. This is in
found no clear relation between filling pressures and E/e'
in a heart failure population (except that most had high
In constrictive pericarditis, the filling pressures are
generally elevated, but longitudinal diastolic function
(e') intact (273
giving a lower E/e' for any given filling pressure.
Left bundle branch block:
And of course, left bundle branch block, as discussed above
Looking at the velocity
and displacement traces, even with the addition of the
protodiastolic motion event, the diastole looks fairly
straightforward, after AVC, the three fundamental phases
known from Doppler flow can be seen: Early filling phase
(E), seen as the first negative phase (e') after AVC,
diastasis with little or no motion, and the atrial systole
(A) seen as the second negative velocity spike (a'). The
atrial displacement of the ring may be described as the
atrium pulling the ring away from the apex, and in
addition the added volume pushed into the ventricle by
atrial (esp. auricular) contraction pushing the
atrioventricular plane. The relative contribution of the
two mechanisms is uncertain.
Taken from the mitral ring, diastolic ventricular
displacement and velocity show the left ventricular diastolic
displacement in the base of the septum,
showing systolic motion toward the apex,
protodiastolic motion away, and the the two
basis diastolic phases, early (e') and late
(a') motion way from the apex, separated by
and strain rate, the pattern can be seen to be
much more complex in these tracings from the
base alone. There are at least four positive
spikes (elongation) during diastole, this is
reflected by much more "steps" towards zero in
the strain curves. As strain
rate is fairly susceptible to noise, this might
have been interpreted as noise (as is the small
negative spikes between) , but integrating to
strain eliminates the random noise, and shows
what is real.
However, using strain and strain rate, the diastole can be
seen to be far more complex, showing a sequence of events
that are different, and with different timing in the
different segments. Thus is seen due to the better
spatial resolution, as deformation imaging eliminates the
effects of the tethering of the base to the more apical
parts. In addition, these events interact, to result in
the simpler pattern seen in motion traces, and the main
finding is that there are more than one peak in each of
the two phases of E and A, and also, the peaks are not
simultaneous in all parts of the ventricle.
An average measure of diastolic strain rate, however, can
be obtained with using a maximal ROI length, in addition
to a maximal strain length, which then will cover at least
of the ventricle
The finding of a complex pattern in diastole, shows that no single strain rate
measurement parameter can be used as a criterion for
. Regional early strain rate
might be taken as an indication of regional diastolic
function, but only if care is taken to identify the
elongation spike, and avoid the return wave. And as the
traces above show, there are differences in both the
amplitude and timing of early diastolic strain rate, the
implication being that there is no meaningful way of
averaging the values into a more global function measure.
The e', being the resultant velocity of the mitral plane,
however, is a truly global measure, being the summation of
all local measurements and taking the time differences
into account, as well as being less pressure dependent, is
a more robust measure of diastolic function as discussed below
For global diastolic
function, diastolic tissue velocity is still the
most important measure, as this is the resultant
global peak measure. This is not the average, but
the resultant of all the local (non-simultaneous)
diastolic strains AND the propagation along the