Group Title: Cardiovascular Ultrasound 2008, 6:57
Title: Comparison of the effect of pressure loading on left ventricular size, systolic and diastolic function in canines with left ventricular dysfunction with preserved and reduced ejection fraction
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Title: Comparison of the effect of pressure loading on left ventricular size, systolic and diastolic function in canines with left ventricular dysfunction with preserved and reduced ejection fraction
Series Title: Cardiovascular Ultrasound 2008, 6:57
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Creator: Lavine SJ
Conetta DA
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Comparison of the effect of pressure loading on left ventricular size,
systolic and diastolic function in canines with left ventricular
dysfunction with preserved and reduced ejection fraction
Steven J Lavine*1,2,3 and Donald A Conettal,2


Address: 1Wayne State University, Detroit, MI 48202, USA, 2University of Florida, Jacksonville, USA and 3Cardiovascular Center, 655 West 8th
Street, Jacksonville, FL 32209, USA
Email: Steven J Lavine* steven.lvine@jax.ufl.edu; Donald A Conetta donald.conetta@jax.ufl.edu
* Corresponding author


Published: 18 November 2008
Cardiovascular Ultrasound 2008, 6:57 doi: 10.1 186/1476-7120-6-57


Received: 26 July 2008
Accepted: 18 November 2008


This article is available from: http://www.cardiovascularultrasound.com/content/6/1/57
2008 Lavine and Conetta; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
Background: Decompensated heart failure may present with severe hypertension in patients with
preserved (PreEF) or reduced left ventricular (LV) ejection fraction (RedEF) and is clinically
indistinguishable. Previously, we demonstrated that arterial pressure elevation increases LV filling
pressures in a canine model of chronic LV dysfunction with PreEF or RedEF. It is not clear whether
any differences in hemodynamics, LV volume or performance, or diastolic function can be
demonstrated between canines with PreEF or RedEF in response to arterial pressure elevation. We
hypothesized that the LV systolic, diastolic, and hemodynamic response to pressure loading would
be similar in RedEF or PreEF.
Methods: We studied 25 dogs with chronic LV dysfunction due to coronary microsphere
embolization with RedEF (35 4%) and 20 dogs with PreEF (50 3%). Arterial pressure was
increased with methoxamine infusion and hemodynamics and echo-Doppler parameters of LV size,
function, transaortic and transmitral pulsed Doppler prior to and with methoxamine infusion was
obtained.
Results: Though LV filling pressures were similar at baseline, LV size was larger (p < 0.01) and
ejection fraction lower in dogs with RedEF (p < 0.001). With methoxamine, there were similar
increases in LV size, LV pressures, and index of myocardial performance with the ejection fraction
reduced similarly. Diastolic parameters demonstrated similar tau increases, E/A reduction, and
diastolic filling shortening in RedEF and PreEF dogs. A similar extent of isovolumic contraction and
relaxation times and index of myocardial performance prolongation occurred with pressure
loading.
Conclusion: Pressure loading in a canine model of LV dysfunction with PreEF and RedEF resulted
in similar degrees of LV dilatation, increased filling pressures, and increased index of myocardial
performance.


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central


cess







Cardiovascular Ultrasound 2008, 6:57


Background
Decompensated heart failure is clinically indistinguisha-
ble in patients with either preserved or reduced left ven-
tricular (LV) ejection fraction and may be accompanied by
elevated arterial pressures. Although systolic dysfunction
is often suspected, it is only after noninvasive imaging that
the clinician discovers that the ejection fraction may be in
the normal range. This may occur in up to 40-50% of
patients depending on age and sex and is more common
in elderly females with diabetes [1,2]. In addition, in
patients with heart failure and LV systolic dysfunction, a
significant though lower percentage of patients also have
hypertension. Using a chronic canine model of LV dys-
function with either preserved or reduced ejection fraction
induced by coronary microsphere embolization, we previ-
ously demonstrated that acute arterial pressure elevation
results in marked elevation of LV filling pressures associ-
ated with prolonged relaxation and shortening of the
diastolic filling period [3,4].

It is not entirely clear whether any differences in hemody-
namics, LV volume or performance, or LV diastolic func-
tion can be demonstrated between canines with reduced
or preserved LV ejection fraction in response to a stressor
(e.g arterial pressure elevation). Although there have been
some information in the literature regarding multiple lev-
els of LV dysfunction, the model employed has been
"tachypacing" induced heart failure, and the heart has
been unloaded or contractile performance improved with
dobutamine [5,6]. Little data has been generated using the
coronary microsphere embolization model which pro-
duces a dilated, scarred left ventricle with reduced LV
systolic function which has relevance to chronic coronary
disease and LV dysfunction [7,8].

We hypothesized that the hemodynamic, LV volume and
functional responses to the stress of pressure loading
would be similar in a model of chronic LV dysfunction
with reduced or preserved LV ejection fraction and would
demonstrate similar elevations of LV filling pressures and
volumes associated with similar direction and extent of
abnormalities in indices describing diastolic function.

Methods
The animals used in this study were maintained in accord-
ance with the guidelines of the Committee on Animal
Studies at Wayne State University School of Medicine and
with the position of the American Heart Association on
research animal use. The study was approved by the
Wayne State University Animal Investigation Committee.
Anesthesia was induced in 45 conditioned mongrel dogs
(16-24 kg) with intramuscular morphine sulfate (1.5 mg/
kg) and acepromazine (1.1 mg/kg) followed in 15 min-
utes by 30 mg/kg of intravenous ketamine hydrochloride.
Maintenance anesthesia was produced by intravenous


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morphine sulfate (1.5 mg/kg/hr) and pentobarbital (3
mg/kg/hr). The dogs were intubated and artificially venti-
lated with a Harvard respirator using room air. Using
fluoroscopic guidance, two 7 F high fidelity catheters
(Millar Instruments) were introduced via the right carotid
artery and advanced to the left ventricle and ascending
aorta. A #8 multipurpose Judkins catheter was introduced
through a sheath (Cordis) into the right femoral artery
and advanced into the left coronary ostium. Continuous
electrocardiographic monitoring was performed using
lead II. At held end expiration, ECG, LV pressures, dP/dt,
and central aortic pressures were obtained at 100 mm/s
using an 8 channel physiologic recorder (Gould). Simul-
taneous 2 dimensional echocardiograms and Doppler
were obtained from with the use of a phased array
echocardiograph (Aloka). Transesophageal 4 and 2 cham-
ber view with color flow were obtained from a 5 MHz
biplane probe placed in the mid-esophagus with both
transaortic and transmitral pulsed Doppler recordings
were obtained from the LV outflow tract and from beyond
the tips of the mitral leaflets in the left ventricle at 100
mm/s.

Model of LV dysfunction with preserved LV ejection
fraction
To test our hypothesis we employed a previously
described canine model of LV dysfunction using coronary
microsphere embolization [7,8]. In the development of
this model, we discovered that the degree of LV dysfunc-
tion produced could be titrated based on microsphere
number per injection, number of injections, and micro-
sphere size. Re-embolization had been required to create
models of moderate LV dysfunction when only minimal
dysfunction had been previously created. Despite mini-
mal systolic dysfunction, there had been remodeling with
increased LV volumes, increased LV mass, and mild LV
filling pressure elevation despite LV ejection fractions
>50% [3,7,9].

LV dysfunction with preserved ejection fraction (PreEF) or
reduced ejection fraction (RedEF) was induced by left
main coronary artery plastic microsphere injections (50
and 80 micron) (3 M) injected in alternating boluses (1
cc) of 17,500 or 12,500 microspheres every 5-10 minutes
until the peak positive dP/dt was reduced by >20% and
the LV end diastolic pressure (LVEDP) was >10 mm Hg
(for PreEF) or the peak positive dP/dt was reduced by
>25% and LVEDP was >13 mm Hg (for RedEF)). Acute LV
dysfunction (LV ejection fraction = 45-50% or 30-35%)
was produced in 45-60 minutes with only minimal or
mild mitral regurgitation (maximal jet area/left atrial area
<20%). At 2 weeks post embolization, echocardiographic
imaging was performed to assess LV systolic function. If
the LV ejection fraction was >55% (for PreEF) or 40% (for
RedEF), the animals were anaesthetized, intubated, and


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Cardiovascular Ultrasound 2008, 6:57


instrumented as above. Additional embolizations were
performed reducing peak +dP/dT an additional 10-20%
or until the LV ejection fraction was <50% (for PreEF) or
<40% (for RedEF) following 45 minutes of stabilization.
At this time, hemodynamics and Echo-Doppler imaging
were repeated as above. This limited embolization
approach ultimately leads to a chronic model of LV dys-
function and increased LVEDP characterized by patchy
myocardial interstitial and replacement fibrosis (7-9)
with an ejection fraction in the normal range (>50%) for
PreEF or ejection fraction in the moderate dysfunction
range (35-40%) for RedEF. Following 45 minutes of sta-
ble hemodynamics, the above parameters were repeated.
The right carotid and femoral arteries were repaired and
the dogs were allowed to recover without any dog suc-
cumbing in the PreEF group and 2 dogs in the RedEF
group in the 1st 48 hours.

At 8 weeks post coronary microsphere embolization, the
animals in both groups were anaesthetized, intubated,
ventilated, instrumented, and imaged as above. Atrial pac-
ing was instituted at least 5 beats above the baseline rate
with a PR interval <160 msec. The above hemodynamics,
cardiac outputs, echocardiographic imaging and Doppler
recordings were obtained after 10 minutes of steady state
pacing. Arterial pressure was increased with a methoxam-
ine infusion to increase LV systolic pressure >40 mm Hg.
Methoxamine was chosen as it increases arterial pressure
without significant change in peak + dP/dT in this model.
The above parameters were again obtained. The pacer was
turned off and the dogs were permitted to return to their
baseline hemodynamic state of chronic LV dysfunction.

Hemodynamic, echocardiographic, and transmitral
doppler measurements
For all stages and time periods, LV pressures, dP/dt, car-
diac outputs, and aortic pressures were measured from the
average of 3 consecutive cycles at held end expiration.
Peak LV systolic pressure, LV minimal pressure, and
LVEDP were measured. The time constant of LV pressure
decline (tau) was calculated using the Weiss method (10).
A frame-by-frame assessment of LV volumes using trans-
esophageal apical views throughout the cardiac cycle was
calculated using the biplane Simpson's rule from the aver-
age of 3 determinations. LV foreshortening rarely occurs
in the canine as compared to humans. LV end diastolic
volume was defined as the largest volume and end systolic
volume as the smallest volume. LV ejection fraction was
calculated as the difference between end diastolic volume
and end systolic volume (stroke volume) divided by end
diastolic volume. LV mass was calculated by the area
length method. Effective arterial elastance was calculated
as LV end systolic pressure/LV end systolic volume.


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For all stages and time periods in both groups of dogs, all
Doppler indices were measured from the average of 3 con-
secutive cycles at held end expiration. From transmitral
Doppler indices, peak rapid filling velocity (E) and peak
atrial filling velocity (A) were measured. The rapid filling
deceleration time was calculated as the time interval from
the peak rapid filling velocity to the time mitral flow
decelerated to the zero baseline. The tracing was extrapo-
lated to the zero baseline if atrial filling commenced prior
to mitral flow fully decelerating to zero. The length of the
diastolic filling period was obtained as the interval from
beginning to the end of transmitral spectral tracing. When
rapid and atrial filling velocity spectra demonstrated any
degree of merging, the onset of atrial filling was defined at
the point of the end of the p wave on the ECG. The time
from the R wave to the end of the mitral time velocity
spectrum and to the onset of the mitral time velocity spec-
trum (onset of flow) was obtained. The severity of mitral
regurgitation was assessed as the ratio of maximal left
atrial color flow jet area during systole divided by the
simultaneous left atrial area.

Index of myocardial performance
Index of myocardial performance (IMP) is defined as the
sum ofisovolumic contraction time and isovolumic relax-
ation time divided by the LV ejection time [3,4,11]. Using
sequential pulse-wave Doppler tracing of the mitral
inflow and transaortic outflow, IMP was calculated:

IMP = (a-b)/b

a = The period of time from the end of transmitral velocity
spectrum of 1 beat to the onset of the transmitral velocity
spectrum of the next beat. b = LVET is time interval from
the onset of the pulsed Doppler transaortic spectrum to
the end of the transaortic spectrum.

The isovolumic relaxation time (IRT) was measured as R
wave to the onset of transmitral velocity spectrum minus
the time from the R wave to the end of the aortic spectral
tracing. The isovolumic contraction time (ICT) was meas-
ured as "a" minus the sum of LV ejection time and IRT.

LV pressure-volume composite plots were constructed for
each stage and time period from mean LV pressures and
LV volumes obtained throughout the cardiac cycle. An
estimate of the operational LV chamber stiffness constant
at end diastole was calculated using the approach of
Marino, et al [12]. Essentially, the difference between LV
pressure minimum and LVEDP was divided by the change
in LV volume from the time of LV pressure minimum to
end diastole.

All calculations were made off-line by the author (SL) and
technical assistants (PP and VJ see acknowledgement)


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Cardiovascular Ultrasound 2008, 6:57


blinded to the dates of the studies, name of the dog, and
experimental conditions. Intra-observer and inter-
observer variability for LV volume was determined by
selecting end diastolic and end systolic frames from the
echocardiogram of 10 previously studied dogs. Each
frame was analyzed 3 weeks apart by 2 observers (see
acknowledgement). The average difference for end diasto-
lic or end systolic volume was 2.2 cc's for intraobserver
variability and 3.4 cc's for inter-observer variability.

Statistics
All data was expressed as mean + standard deviation. Dif-
ferences between a variable among stages was assessed
using analysis of variance for repeated measures. If the F
statistic (p < 0.05) indicated a significant difference, then
Tukey's test was utilized to determine where the signifi-
cant differences existed. A p < 0.05 was considered signif-
icant.

Results
Table 1 1 summarizes parameters of LV size, systolic and
diastolic function, and LV pressures at baseline and fol-
lowing induction of either chronic LV dysfunction with
PreEF or RedEF in canines. LV size and mass increased, LV
ejection fraction declined, LV filling pressures increased,
and tau was prolonged in both groups following the
induction of LV dysfunction. LV end diastolic and end
systolic volumes were greater (p < 0.01) and the LV ejec-
tion fraction was further reduced in the RedEF group as
compared to the PreEF group as per the design (p <
0.001). Despite, the lower ejection fraction and larger LV
volumes, LVEDP and LV minimal pressures were similar
in both the PreEF and RedEF groups. Transmitral Doppler
parameters describing diastolic function revealed a reduc-
tion in deceleration time, and increases in IRT and ICT in
both groups. IMP demonstrated an increase in both
groups with a greater increase in the RedEF group (p <
0.05). This was due to a non-significantly greater IRT and
ICT in the RedEF group. Mitral regurgitation was noted in
3 dogs with PreEF (minimal or mild in all 3 dogs; jet area/
left atrial area = 4%, 5%, and 9%) and 5 dogs with RedEF
(minimal or mild in 5 dogs; jet area/left atrial area = 2%,
5%, 7%, 8%, and 11%)

Table 2 1 summarizes the results of arterial pressure incre-
mentation with methoxamine in both groups. LV vol-
umes increased with a reduction of LV ejection fraction in
both groups. Stroke volume declined only in the RedEF
group. LVEDP and LV minimal pressures, effective arterial
elastance and chamber stiffness increased in both groups.
Effective arterial elastance was lower in the RedEF group at
baseline LV dysfunction (p < 0.05) and with pressure
loading (p < 0.05) than in the PreEF group. Figure 1 dis-
plays composite LV pressure-volume plots (with mean
standard error of the mean) prior to and following meth-


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examine infusions for PreEF (left) and RedEF (right)
groups. Both groups demonstrate a similar rightward and
upper shift of the pressure-volume curve from the base-
line LV dysfunction plot. LV volumes (p < 0.01) were
greater and LV ejection fraction (p < 0.001) were further
reduced in the RedEF group than the PreEF group with
arterial pressure elevation. Table 3 summarizes the
results of arterial pressure elevation in both groups with
regard to diastolic filling parameters, IMP and its compo-
nents. For both groups, E and E/A declined, the time to
onset of mitral velocity was delayed, and was associated
with shortening of diastolic filling, prolongation of IRT
and ICT with marked increases in IMP. The IMP value
with pressure loading was significantly more elevated in
the RedEF group. Figure 2 and 3 summarizes the individ-
ual canine response in each group to pressure loading
with regard to IMP and diastolic filling period (figure 2)
and IRT and ICT (figure 3). The responses of each of these
parameters to pressure loading were similar in both
groups of dogs. Mitral regurgitation was noted in 5 dogs
with PreEF with methoxamine infusion (mild in all; jet
area/left atrial area = 6%, 6%, 8%, 10%, and 11%) and 8
dogs with ReEF (mild in all; 6%, 7%, 9%, 11%, 12%,
14%, 15% and 17%)

Table 4 1 summarizes the changes in parameters with pres-
sure loading in both the PreEF and RedEF groups. The
direction, quantity, and percentage (data not shown)
change in each parameter with arterial pressure elevation
was similar in both canine LV dysfunction groups.

Discussion
In this study we used a chronic canine model of LV dys-
function with elevated LVEDP's induced by coronary
microsphere embolization with either a PreEF or RedEF to
determine whether a stressor to LV performance would
produce differences in hemodynamics, LV volume and
systolic performance, and diastolic function. Methoxam-
ine infusion was administered to increase arterial pressure
>40 mm Hg above baseline. The effect of arterial pressure
elevation on LV volumes, LV filling pressures, parameters
of diastolic function, and IMP were determined.

This model of LV dysfunction is ideal as the level of LV
dysfunction can be titrated based on the dosage of coro-
nary microspheres and the number of different times the
procedure is performed (7,8). Pressure loading resulted in
identical increases in LV filling pressures associated with
similar delays in the onset of diastolic filling, shortening
of diastolic filling, and increases in isovolumic times.
Consequently, LV filling volumes entered a poorly relaxed
left ventricle at higher left atrial pressures at the time of
mitral opening [3]. Changes in parameters of LV volume,
systolic function, LV filling pressures and hemodynamics
were similar as shown in table 4 despite LV volumes and


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Pressure-Volume Loops Prior to and Following Pressure Loading


PRESERVED LV EF


* LVD PreEF
* LVD methox


REDUCED LV EF


* LVD Red EF
* LVD methox


0 10 20 30 40 50 60 70 80 90 100
LV Volume (cc)


* LVD
* LVD


0 10 20 30 40 50 60 70 80 90 100
LV Volume (cc)


* LVD Red EF
* LVD-methox


0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100
LV Volume (cc) LV Volume (cc)


Figure I
Composite LV pressure-volume plots (mean standard error of the mean) at paced LV dysfunction and with
peak methoxamine (LVD-methox) are shown for canines with LV dysfunction and preserved LV ejection frac-
tion (LVD-PreEF) on the left and LV dysfunction with reduced ejection fraction (LVD Red EF) on the right.
Below are the expanded LV pressure-volume plots truncated at 40 mm Hg to demonstrate diastolic pressure differences more
clearly. The pressure-volume curves are shifted rightward and upward for both groups of dogs. LV volumes are greater at both
baseline LV dysfunction and with methoxamine in the group with reduced ejection fraction.


IMP being larger and ejection fraction lower in the RedEF
group prior to pressure loading. Changes in effective arte-
rial elastance and operational LV chamber stiffness were
similar as were qualitative changes in the composite LV
pressure-volume plots. In summary, hemodynamic, LV
volume, LV pressures, and diastolic changes were indistin-
guishable.

Previous Literature
Using pressure-volume plots, the effect of pressure load-
ing on LV dysfunction has been well described both clini-
cally and experimentally [4,13]. However, only a modest
amount of information is available for various levels of LV
dysfunction and only in the model produced by rapid
ventricular pacing [5,6]. Rahko [5] demonstrated that the


position of the pressure-volume plot changed with vary-
ing levels of LV dysfunction as did the slope of the rela-
tion. However, he used inferior vena caval occlusion and
the extent of LV dysfunction was not stable for an
extended period of time as occurs with coronary micro-
sphere embolization [7,8]. Pressure loading in the pacing
model might have resulted in similar rightward shifts of
the pressure-volume plot (with varying levels of LV dys-
function) with similar changes in effective chamber com-
pliance as compared to the coronary microsphere model.
The expected increases in LV volumes with both levels of
LV dysfunction may induce pericardial constraint result-
ing in a similar rightward and upward shift in the pres-
sure-volume plot [14]. Moe [6] studied the recovery from
pacing induced LV dysfunction and demonstrated a



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Cardiovascular Ultrasound 2008, 6:57


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Effect of Pressure Loading on Index of Myocardial Performance
and the Diastolic Filling Period


Preserved EF


/

I



I i


LVDys Pressure Loading


c


20

-
1 25
|-


20
a-






-
550
500



450
S400
350
300

.r 250
S200
550
S 500
Co
E 450
*g 400
' 350
a-
250
LL 200
= 150
0
m 100


c
W 25
E
20



00






S450
a-














400


300
250




500

- 00
600
550
0) 500
E 450
2 400
50
a0
300
250
LZ 200 -
= 150
0
o 100


LVDys Pressure Loading


Reduced EF




//I
/ *
-

} -


LVDys F


pressuree Loading


.



L



P i
LVDys Pressure Loading


Figure 2
Index of myocardial performance at baseline LV dysfunction (LVDys) and following pressure loading in dogs
with LV dysfunction and preserved LV ejection fraction (left upper) and heart failure with reduced ejection
fraction (right upper) demonstrates similar extent of increases with pressure loading. Also, the diastolic filling
period at baseline LV dysfunction and following pressure loading in dogs with LV dysfunction and preserved ejection fraction
(left lower) and LV dysfunction with reduced ejection fraction (right lower) demonstrates a similar degree of shortening with
pressure loading.


downward shift in the velocity of circumferential shorten-
ing-end systolic stress plot with recovery. However, this
study did not stress the left ventricle. Pressure-volume
studies in pacing induced heart failure using afterload
augmentation with phenylephrine and dobutamine aug-
mentation also demonstrated a reduction in ventricular
arterial coupling [15], but the effect of multiple levels of
stable LV dysfunction were not addressed. Unfortunately,
phenylephrine is also a positive inotrope initially unless
beta blockade is used ([16] and personal observations).
Using an isolated heart cross-perfused model of LV dys-
function previously produced by coronary microemboli-
zation, Todaka [17] demonstrated that the end diastolic
pressure-volume relation was shifted rightward. However,


multiple levels of LV dysfunction and afterload stress were
not employed. Consequently, there is a paucity of studies
examining the effects of afterload stress on LV systolic and
diastolic performance with more than 1 level of LV dys-
function. This study served to help fill this void and points
out that though the resting diastolic pressure-volume
plots may differ in position in that more severe LV dys-
function is shifted rightward, the response to pressure
loading is hemodynamically similar. The coronary micro-
sphere model of LV dysfunction is uniquely suited to
explore this issue as both varying levels of LV dysfunction
can be produced for prolonged periods of time [7,8] and
responses to pharmacologic interventions can be assessed
[18]. Furthermore, this model can also be used to assess


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F>









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Effect of Pressure Loading on Isovolumic Time Intervals


Preserved EF


Pressure Loading


Reduced EF


200
) 180
E
S160
E
* 140
C 120
100
E wo
80
O 60
.2
E 40
0 20
0
0 0


300
0)
E 250
1)
E
* 200
0
S 150
X

DC 100
.2
E
. 50
0
0


, 200
a0
) 180
E
160
E 140
I--
S120


o
o 100
80
0
0 60
E 40

20
0 0
Q

300

E 250
1)
E
F 200

150
X
0_
DC 100

E
M 50
0
_T 0


I7
.-


LVDvs


Pressure Loading


ii
Li



Pro




LVDys Pressure Loading


Figure 3
Isovolumic contraction time at baseline LV dysfunction (LVDys) and following pressure loading in dogs with
LV dysfunction and preserved ejection fraction (left upper) and LV dysfunction with reduced ejection fraction
(right upper) demonstrates similar extent of increases with pressure loading. Similarly, the isovolumic relaxation
period at baseline LV dysfunction (LVDys) and following pressure loading in dogs with LV dysfunction and preserved ejection
fraction (left lower) and LV dysfunction with reduced ejection fraction (right lower) demonstrates a similar degree of lengthen-
ing with pressure loading.


the force frequency relationship which may trend down-
ward at higher rates with various causes of LV dysfunction
[19].


Patients with decompensated heart failure commonly
present in the emergency room with marked increases in
arterial pressure. It is only after noninvasive evaluation of
the LV ejection fraction that clinicians discover that the
ejection fraction may be preserved or in the normal range.
Heart failure with normal or PreEF has an increased pro-
portion of elderly females and associated hypertension
with rates of morbidity and mortality that have been
described as either lower or equivalent to patients with
RedEF [20-23]. It has been difficult to distinguish between
PreEF and RedEF clinically in the presentation of acute


decompensated heart failure. Acute decompensated heart
failure may present as 1 of 3 presentations: cardiogenic
shock, decompensation of chronic heart failure, and pul-
monary edema with hypertension [24]. The ADHERE reg-
istry demonstrated at least 50% of patients and the Euro
Heart Survey II described 34% of patients with decompen-
sated heart failure presented with PreEF with lower mor-
tality than patients with reduced ejection fraction though
subsets of patients (reduced systolic blood pressure and
renal insufficiency) had comparable mortality [22,25].


Studies attempting to differentiate PreEF from RedEF at
the time of acute decompensation have been limited to
surveys and registries. As the pathophysiology of this pres-
entation is still not well understood, clinical or experi-




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LVDys Pressure Loading







Cardiovascular Ultrasound 2008, 6:57


mental trials addressing this issue have not yet been
performed. As hypertension appears as an important co-
morbidity, it stands to reason that it may participate in its
pathogenesis. Reviews of therapy for decompensated
heart failure have suggested normalizing blood pressure,
diuresis, use of either angiotensin converting enzyme
inhibitors or angiotensin receptor blockers, beta blockers,
aldosterone inhibitors, and possibly nitrates for therapy
[26-28]. Many of the above agents are useful in both heart
failure with RedEF and PreEF especially agents that pro-
mote regression of LV hypertrophy, avoidance of tachycar-
dia [29], reduction in interstitial collagen and reduction
in the renin angiotensin system activity [30].

Limitations
First, the appropriateness of the coronary microemboliza-
tion model for the production of LV dysfunction is open
to question. As the microsphere model of LV dysfunction
results in diffuse fibrotic changes throughout the myocar-
dium, its histopathology bears great similarity to the his-
topathology seen in hypertensive and diabetic
cardiomyopathy [31,32], ischemic cardiomyopathy, and
hypertensive heart disease with and without LV dysfunc-
tion. The applicability to all patients with heart failure and
PreEF (ejection fraction >40%) is open to question. It has
applicability to the group of patients with hypertensive
heart disease as the etiology of heart failure. Alternatively,
the use of a renovascular model of hypertension in aged
dogs produces an excellent model (increased myocardial
fibrosis) of LV dysfunction with PreEF for testing where
hypertensive heart disease is the etiology of heart failure
[33]. This study does not address the issue of the appropri-
ateness of whether the etiology and pathogenesis of heart
failure with PreEF or RedEF should be different. This study
is simply assessing the hemodynamic and LV volume and
function response to pressure loading in experimental
groups based on LV ejection fraction. Certainly, the etiol-
ogy may be the same or different for both heart failure
with PreEF and RedEF. However, there is similarity of
hemodynamic, LV volume, systolic and diastolic
responses with PreEF vs RedEF.

Second, one must raise the question whether pressure
loading is the appropriate stressor. Earlier studies using
volume loading increased LV size and LV filling pressures
but lengthened LV ejection time [34]. Patients with LV
dysfunction often have increased IMP's due to lengthen-
ing of the isovolumic indices and shortening of LV ejec-
tion time [11,35]. Also, pressure loading increases IMP by
lengthening the isovolumic indices and insignificantly
shortening LV ejection time [3,4], a finding that mirrors
the expected findings in a patient with severe LV systolic
function. Finally, a substantial number of patients present
with pulmonary edema and hypertension who rapidly
respond to lowering of their arterial pressure and have


http://www.cardiovascularultrasound.com/content/6/1/57



PreEF or RedEF [20,22]. However, methoxamine may not
be a pure afterload stressor as 1 study has suggested that it
may increase preload to a greater extent than angiotensin
II [36]. In addition, an alpha adrenergic agonist may also
increase contractility [37] though peak positive dP/dT was
unchanged in this study with methoxamine infusion.

Third, as this is an experimental study, the applicability of
these findings and relation to humans is always a limita-
tion. The general anesthesia utilized may influence the
results, and the results may differ with conscious canines.
However, this anesthesia regimen has been used in
numerous studies in our laboratory and results in lower
arterial pressures and LV filling pressures, which may
lessen the impact of our intervention. Nevertheless, the
experimental data cited here clearly indicates that there is
little hemodynamic difference to pressure loading based
on LV ejection fraction. This is clearly paralleled clinically
by our experience in the emergency room when patients
who are severely hypertensive and present with acute
decompensated heart failure. There are few clinical cues as
to whether the LV ejection fraction is normal or reduced.
The importance of blood pressure control may assume
even greater importance in patients with hypertensive
heart disease and symptoms of heart failure.

Conclusion
Pressure loading in a canine model of LV dysfunction with
PreEF or RedEF resulted in similar degrees of LV dilata-
tion, increased filling pressures, and increased IMP associ-
ated with similar delays in isovolumic relaxation and
contraction despite a larger left ventricle and a lower ejec-
tion fraction in the RedEF group.

Abbreviations
LV: left ventricular; PreEF: preserved ejection fraction;
LVEDP: left ventricular end diastolic pressure; RedEF:
reduced ejection fraction; E: peak rapid filling velocity; A:
peak atrial filling velocity; IMP: index of myocardial per-
formance; IRT: isovolumic relaxation time; ICT: isovolu-
mic contraction time.

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
SL designed the study, carried out the experimental proto-
col, analyzed the data, and wrote the manuscript. DC
assisted in the drafting and revising of the manuscript,
provided criticism of the results as they pertain to existing
literature, and approved the final version submitted.







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Cardiovascular Ultrasound 2008, 6:57


Additional material


Acknowledgements
We would like to thank the American Heart Association of Michigan for
their support. We would like to thank Petar Prcevski D.V.M. and Vicki
Johnson for both their invaluable technical assistance and the echocardio-
graphic analysis in this investigation

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