Group Title: Cardiovascular Ultrasound 2006, 4:45
Title: Effect of changes in contractility on the index of myocardial performance in the dysfunctional left ventricle
CITATION PDF VIEWER THUMBNAILS PAGE IMAGE ZOOMABLE
Full Citation
STANDARD VIEW MARC VIEW
Permanent Link: http://ufdc.ufl.edu/UF00100203/00001
 Material Information
Title: Effect of changes in contractility on the index of myocardial performance in the dysfunctional left ventricle
Series Title: Cardiovascular Ultrasound 2006, 4:45
Physical Description: Archival
Creator: Lavine SJ
Publication Date: 39038
 Record Information
Bibliographic ID: UF00100203
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: Open Access: http://www.biomedcentral.com/info/about/openaccess/

Downloads

This item has the following downloads:

effect_of_changes ( PDF )


Full Text



Cardiovascular Ultrasound


0
BioMed Central


Research

Effect of changes in contractility on the index of myocardial
performance in the dysfunctional left ventricle
Steven J Lavine*


Address: Department of Medicine, Division of Cardiology, Wayne State University and University of Florida/Jacksonville, Detroit, Michigan and
Jacksonville, Florida, USA
Email: Steven J Lavine* steven.lvine@jax.ufl.edu
* Corresponding author


Published: 17 November 2006
Cardiovascular Ultrasound 2006, 4:45 doi: 10.1 186/1476-7120-4-45


Received: 08 October 2006
Accepted: 17 November 2006


This article is available from: http://www.cardiovascularultrasound.com/content/4/1/45
2006 Lavine; 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: The index of myocardial performance has prognostic power in patients with
cardiomyopathy and following myocardial infarction. As the index of myocardial performance has
been shown to be preload and afterload dependent, the effect of altering contractility on IMP and
its components with left ventricular dysfunction has been incompletely delineated.
Methods: Chronic left ventricular dysfunction was induced in 10 canines using coronary
microsphere embolization. Each dog was instrumented and imaged with 2D echo and Doppler. At
the same atrially paced rate, contractility was increased with a dobutamine infusion and then
following 4 weeks of oral digoxin.
Results: With chronic left ventricular dysfunction, a reduced left ventricular ejection fraction (42
3%, p < 0.001) and increased index of myocardial performance (0.58 0.17, p < 0.01) due to
isovolumic contraction time lengthening and shortened left ventricular ejection time were noted.
Dobutamine increased ejection fraction (p < 0.001), reduced left ventricular end diastolic pressure
(p < 0.01), and reduced the index of myocardial performance (0.33 0.17, p < 0.001) due to
isovolumic contraction time, isovolumic relaxation time, and left ventricular ejection time
shortening. Digoxin increased ejection fraction (p < 0.05), reduced left ventricular end diastolic
pressure (p < 0.05), and reduced the index of myocardial performance (0.42 0.13, p < 0.01) due
to isovolumic contraction time shortening (p < 0.001). Both dobutamine and digoxin lengthened
the diastolic filling period (p < 0.01).
Conclusion: Increased inotropy with digoxin and dobutamine reduced the index of myocardial
performance in dogs with left ventricular dysfunction. Shortened isovolumic contraction time,
increased diastolic filling period, and reduced left ventricular end diastolic pressure with digoxin
may provide insight into its efficacy in heart failure.


Background
The index of myocardial performance (IMP), calculated as
the sum of the isovolumic relaxation time (IRT) and iso-
volumic contraction time (ICT) divided by the left ven-


tricular (LV) ejection time (LVET), has been utilized as a
combined systolic-diastolic index that is prognostic in
patients with dilated cardiomyopathy [1] and post myo-
cardial infarction [2]. Its predictive value appears to be


Page 1 of 8
(page number not for citation purposes)







Cardiovascular Ultrasound 2006, 4:45


related to shorter isovolumic indices and preserved LV
ejection time (LVET). In the original description of this
index in patients with normal LV function and dilated car-
diomyopathy, IMP was correlated with indices of systolic
performance and contractility but was unrelated to heart
rate, preload, and mean arterial pressure [3]. It has been
further demonstrated that contractility and systolic per-
formance were related to IMP in studies which utilize
dobutamine in the normal left ventricle [4,5], in the left
ventricle with reduced LV function [6,7] with contractile
reserve, with the ischemic production of LV dysfunction
[8], or in groups with differing LV function [1,3]. Of
importance, dobutamine was demonstrated to shorten all
components of IMP but specifically ICT and prolonged
the diastolic filling period both in the normal ventricle [5]
and in the left ventricle with dysfunction and contractile
reserve [6,7].

Systematic evaluations of IMP in the normal and abnor-
mal left ventricle have recently been performed using a
canine model of chronic ischemic LV dysfunction. IMP
was demonstrated to be preload and afterload dependent
but not heart rate dependent [9,10]. In this model,
improved systolic performance with afterload reduction
with LV dysfunction was associated with shortening of the
isovolumic indices and lengthening of the LVET [12].
Although clinical studies [6,7] have been performed
assessing the effect of dobutamine stress on IMP with LV
dysfunction, the focus has been on ischemia or contractile
reserve. Limited work has been performed assessing the
effect of contractility on IMP and its components with LV
dysfunction without the obfuscating effects of intraven-
tricular conduction delay or ischemic provocation [6,7].

Digoxin, an oral inotropic agent, also has beneficial symp-
tomatic effects in heart failure patients with either reduced
or preserved LV function [11]. However, the influence of
digoxin on IMP is unknown and may provide some
insight into its efficacy.

The goals of this study were: [1] to determine the effects of
increased contractility on IMP and its components; and
[2] to determine whether digoxin, a weak inotrope with-
out an adverse survival benefit, affects IMP and its compo-
nents. With LV dysfunction, we hypothesize that inotropic
agents reduce the IMP by shortening isovolumic indices
and possibly lengthening LVET (due to increased stroke
volume) with a resultant increase in diastolic filling
period. To assess this hypothesis, we used a canine model
of chronic ischemic LV dysfunction producing only mild
systolic dysfunction with elevated LV filling pressures
where ischemia with inotropic stimulation was unlikely.


http://www.cardiovascularultrasound.com/content/4/1/45



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 protocol was approved by the
Animal Investigation Committee of Wayne State Univer-
sity. Anesthesia was induced in 10 conditioned mongrel
dogs (16-24 kg) with intramuscular morphine sulfate
(1.5 mg/kg) and acepromazine (1.1 mg/kg) followed in
15 minutes by 30 mg/kg of intravenous ketamine hydro-
chloride. Maintenance anesthesia was produced by intra-
venous morphine sulfate (1.5 mg/kg/hr) and
pentobarbital (3 mg/kg/hr). The dogs were intubated and
artificially ventilated with a Harvard respirator using
room air. Using fluoroscopic guidance, two 7F high fidel-
ity catheters (Millar Instruments) were introduced via the
right carotid artery and advanced to the left ventricle and
ascending aorta. A #7 multipurpose Judkins catheter was
introduced through a sheath (Cordis) into the right femo-
ral artery and advanced into the left coronary ostium.
Continuous electrocardiographic monitoring was per-
formed 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). Simultaneous 2 dimensional echocar-
diograms and Doppler were obtained from with the use of
a phased array echocardiograph (Aloka 880). Trans-
esophageal 4 chamber view was obtained from a 5 MHz
probe placed in the mid-esophagus. 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. Mitral
regurgitation was assessed from the 4-chamber view as the
size of the maximal color flow jet divided by the left atrial
area.

Induction of LV dysfunction
Ischemic LV dysfunction was induced by left main coro-
nary artery plastic microsphere injections (58 2
microns) (3M) injected in boluses of 17,500 micro-
spheres every 5-10 minutes until the peak positive dP/dT
was reduced by 25% and the LV end diastolic pressure was
>12 mm Hg. LV dysfunction (LV ejection fraction = 35-
40% acutely and >40% chronically) was produced in 45-
60 minutes with only mild mitral regurgitation (maximal
color flow jet area/left atrial area <20%). This approach
ultimately leads to a model of chronic LV dysfunction
where the extent of LV dysfunction may be titrated [12].
Following 45 minutes of stable hemodynamics, the above
parameters were repeated. The right carotid and femoral
arteries were repaired and the dogs were allowed to
recover without any dog succumbing. The dogs were fol-
lowed carefully for 8 weeks prior to re-study. This time
period was chosen as this model has previously demon-


Page 2 of 8
(page number not for citation purposes)







Cardiovascular Ultrasound 2006, 4:45


strated interstitial and replacement fibrosis without evi-
dence of necrosis or inflammation at 8 weeks post
embolization [12].

At 8 weeks post coronary microsphere embolization, the
animals were anaesthetized, intubated, instrumented, and
ventilated as above. Using fluoroscopy, a #7 thermodilu-
tion catheter and a #5 bipolar pacing wire were advanced
from the left internal jugular vein to the pulmonary artery
and right atrium respectively. Atrial pacing commenced
10 beats above baseline rate with a PR interval <160 msec.
Transthoracic and transesophageal echocardiography and
Doppler were obtained as above. Continuous electrocar-
diographic monitoring was performed using lead II. The
above hemodynamic, echocardiographic, and Doppler
parameters were obtained after 10 minutes of steady state
atrial pacing. Dobutamine was infused at a rate of 2-2.5
micrograms/kg/minute for 15 minutes. Care was taken to
adjust the rate of infusion to ensure that atrial pacing was
maintained. The above parameters were then obtained.
The infusion was discontinued and the dogs were
observed until hemodynamics and echocardiographic
assessment of LV systolic function returned to the pre-
dobutamine LV dysfunction baseline. The above parame-
ters were then obtained as a baseline for digoxin therapy.
The vessels were repaired, and the animals were recovered.

On the following day, each dog received 0.02 mg/kg/dig-
oxin in their food daily to a maximal dose of 0.25 mg dig-
oxin for 4 weeks [13,14]. At 1 and 2 weeks, digoxin levels
were ascertained to ensure that blood levels were non-
toxic. After 4 weeks of therapy, the animals were anaesthe-
tized, intubated, ventilated, and instrumented as above.
Atrial pacing commenced at the same rate as with dob-
utamine and hemodynamics, echocardiography and Dop-
pler were obtained as above. The animals were then
sacrificed.

Control dogs
LV dysfunction was induced in 8 additional dogs as
described above. At 8 and 12 weeks post embolization,
the dogs were instrumented as described above. Hemody-
namics, echocardiography, spectral, and color Doppler
were obtained at baseline and with atrial pacing 10 beats
above baseline. The same atrial rate was used for each dog
at 8 and 12 weeks post embolization.

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. The
time constant of LV pressure decline was calculated using
the Weiss method [15]. LV end diastolic and end systolic
volumes were calculated using Simpson's Rule from the


http://www.cardiovascularultrasound.com/content/4/1/45



average of 3 determinations. LV ejection fraction was cal-
culated as the difference between end diastolic volume
and end systolic volume divided by end diastolic volume.
LV mass was calculated by the area length method as per
the recommendations of the American Society of Echo
[16].

For all stages and time periods, all Doppler indices were
measured from the average of 3 consecutive cycles at held
end expiration. From transmitral Doppler indices, peak
rapid filling velocity (E) and peak atrial filling velocity (A)
were measured. The E/A ratio was calculated. The rapid
filling deceleration time was calculated as the time inter-
val from the peak rapid filling velocity to the time mitral
flow decelerated to the zero baseline. The tracing was
extrapolated to the zero baseline if atrial filling com-
menced prior to mitral flow fully decelerating to zero.
Diastolic, rapid filling, and atrial filling velocity integrals
were determined. Mitral regurgitation was assessed using
the ratio of the maximal color flow jet area in the left
atrium during systole divided by the left atrial area.

Index of myocardial performance
From the transmitral pulsed Doppler, the time interval
between the end of mitral filling and the onset of mitral
filling was determined ("a"). From transaortic pulsed
Doppler, the time interval from the beginning of aortic
flow to the end of aortic flow was determined ("b" or
LVET). The IMP can be calculated as

IMP = (a-b)/b

To determine the IRT, the time from the R wave to the end
of aortic flow was subtracted from the R wave to the onset
of mitral flow interval. As "a-b" represents total isovolu-
mic time, the ICT is the difference between IRT and "a-b"
[3]. The ICT, IRT, and LVET indexes were calculated to cor-
rect for differing heart rates by dividing the value by the
square root of the RR interval (for non-paced compari-
sons).

Intraobserver variability for calculation of IMP was deter-
mined from 25 randomly selected stages. Each determina-
tion was performed 4 weeks apart. The average difference
between determinations was 0.008 0.002. Intraobserver
and interobserver variability for LV echocardiographic
volume was determined by selecting end diastolic and
end systolic frames from the echocardiogram of 10 previ-
ously studied dogs. Each frame was analyzed 3 weeks
apart by 2 observers (see acknowledgement). The average
difference for end diastolic or end systolic volume was 2.2
0.9 cc for intraobserver variability and 3.4 1.7 cc for
interobserver variability.




Page 3 of 8
(page number not for citation purposes)








Cardiovascular Ultrasound 2006, 4:45

Statistics
All data was expressed as mean + standard deviation. Dif-
ferences between a variable among stages was assessed
using paired T testing. A p < 0.05 was considered to be sig-
nificant.

Results
Table 1 summarizes the hemodynamics, LV size and func-
tion parameters, transmitral Doppler and IMP at baseline
and with chronic LV dysfunction. With chronic LV dysfunc-
tion, LV volumes, LV mass, heart rate, and LV end diastolic
pressure were increased. Ejection fraction and peak +dP/
dT declined. Parameters of relaxation (Tau and E/A) were
also abnormal as compared to baseline. The deceleration
time was also shortened suggesting reduced LV chamber
compliance. This finding may be secondary to the intersti-
tial and replacement fibrosis seen in the myocardium with
this model of chronic LV dysfunction [12]. IMP was
increased as compared to baseline (Figure 1) due to insig-
nificant prolongation of IRT (p = 0.18), prolongation of
ICT, and LVET shortening. At baseline, 2 of 10 dogs had
trivial mitral regurgitation (jet area/left atrial area <5%).
With LV dysfunction, 3 dogs had trivial or mild mitral
regurgitation (jet area/left atrial area = 4%, 5%, and 8%).

Table 2 summarizes the above parameters with paced LV
dysfunction and for dobutamine infusion. As expected,
dobutamine increased peak +dP/dT, stroke volume, and
ejection fraction with a reduction in LV end diastolic pres-
sure. Dobutamine improved LV relaxation and LV cham-
ber compliance (as characterized by lengthening of the


http://www.cardiovascularultrasound.com/content/4/1/45


1.0

0.9

0.8 -

0.7

0.6

0.5

0.4
p=0.0062
0.3

0.2

0.1
Base LV Dys
Stage

Figure I
The Effect of chronic LV dysfunction on IMP: The IMP is plot-
ted for each dog (y axis) at baseline (base) and following the
development of chronic LV dysfunction (LV Dys). With
chronic LV dysfunction, each dog demonstrated an increase
IMP.





deceleration time). IMP declined (Figure 2) due to
marked shortening of the ICT, shortening of IRT, and
shortening of LVET. Mitral regurgitation was noted in 1 of
10 dogs with dobutamine (jet area/left atrial area = 6%)


Table I: Hemodynamics, LV size, tra
Doppler, and IMP at baseline and wil


LV End Diastolic Volume (cc)
LV End Systolic Volume (cc)
Stroke Volume (cc)
LV Ejection fraction (%)
LV Mass (g)
LVSP (mm Hg)
LVEDP (mm Hg)
Cardiac Output (I/min)
Peak +dP/dT (mm Hg/sec)
Tau (msec)
E/A
Heart rate (beats/min)
Deceleration Time (msec)
ICT index (msec)
IRT index (msec)
LV ejection time index (msec)
IMP


nsmitral and transaortic Table 3 summarizes the above parameters with paced LV
th chronic LV dysfunction dysfunction and with digoxin administration. Digoxin
administration resulted in an increased LV ejection frac-
Baseline Chronic LVD tion, stroke volume, and peak +dP/dT associated with a

41 - 5 54 8 decline in LV end diastolic pressures. The diastolic filling
15 4 31 12** period prolonged without change in other diastolic func-
26 3 23 9 tion parameters measured. IMP declined in 9 of 10 dogs
63 9 42 3*** (Figure 3) primarily secondary to ICT shortening (>60%
61 10 85 1 I*** reduction). Mitral regurgitation was noted in 2 dogs with
109 14 111 12 digoxin (jet area/left atrial area = 5%, 6%). Table 4 sum-
6.2 2.3 I 1.8 4.9**
6.2 2.3 11.8 4.9* marizes the hemodynamics, LV size and function param-
3.1 0.7 2.8 0.4
1874 244 1388 206** eters, transmitral Doppler and IMP 8 and 12 weeks post
24 6 39 5*** embolization. There were no significant differences
2.1 1.3 1.5 0.4* between parameters measured at 8 and 12 weeks in con-
78 12 93 18* trol dogs strongly supporting the stability of this model.
217 38 129 36* Mitral regurgitation was seen in 1 of 8 dogs at both 8 and
40 22 58 31*
46 22 58 31* 12 weeks (jet area/left atrial area = 5% at 8 weeks and 4%
226 23 201 24* at 12 weeks post embolization).
226 23 201 24* at 12 weeks post embolization).


0.38 0.14


0.60 0.19**


Abbreviations: E/A = peak rapid filling velocity/peak atrial filling
velocity; ICT = isovolumic contraction time; IRT = isovolumic
relaxation time; IMP = Index of myocardial performance; LVSP = LV
systolic pressure; LVD = LV dysfunction; LVEDP = LV end diastolic
pressure.
Statistics:*p < 0.05, **p < 0.01, ***p < 0.001 vs Baseline;


Discussion
IMP has been identified as a useful prognostic parameter
following acute myocardial [2,17,18] infarction, with
dilated cardiomyopathy [1], amyloid heart disease [19],
and pulmonary hypertension [20]. Its prognostic capabil-
ities appear to be mediated by increased values due to
longer isovolumic indices and a shorter LVET. Despite its
apparent clinical performance, IMP is preload and after-
Page 4 of 8
(page number not for citation purposes)









Cardiovascular Ultrasound 2006, 4:45


Table 2: Hemodynamics, parameters of LV size, transmitral and
transaortic Doppler, and IMP with LV dysfunction and with
dobutamine


http://www.cardiovascularultrasound.com/content/4/1/45



Table 3: Hemodynamics, parameters of LV size, transmitral and
transaortic Doppler, and IMP with LV Dysfunction and with
digoxin


LV End Diastolic Volume (cc)
LV End Systolic Volume (cc)
Stroke Volume (cc)
LV Ejection fraction (%)
LVSP (mm Hg)
MAP (mm Hg)
LVEDP (mm Hg)
Peak +dP/dT (mm Hg/sec)
Tau (msec)
E (cm/s)
A (cm/s)
E/A
Heart rate (beats/min)
DFP (msec)
DVI (cm)
Deceleration Time (msec)
ICT index (msec)
IRT index (msec)
LV ejection time index (msec)
IMP


Paced LV
Dysfunction


55 7
32 7
23 6
42 3
110 12
100 10
I 1.8 2.4
1438 279
37 6
81 24
55 29
1.9 0.7
102 7
296 54
12.6 2.4
148 30
55 30
63 25
204 22
0.59 0.17


Dobutamine


51 8
18 5***
33 7***
65 10***
109 7
93 9
7.5 2.1**
2250 148***
25 7***
II I 16***
54 19
2.3 0.8
102 7
364 38***
16.7 2.5***
201 46**
17 10***
44 22*
186 28*
0.33 0.17***


Paced LV Dysfunction Digoxin


LV End Diastolic Volume (cc)
LV End Systolic Volume (cc)
Stroke Volume (cc)
LV Ejection fraction (%)
LVSP (mm Hg)
MAP (mm Hg)
LVEDP (mm Hg)
Peak +dP/dT (mm Hg/sec)
Tau (msec)
E (cm/s)
A (cm/s)
E/A
Heart rate (beats/min)
DFP (msec)
DVI (cm)
Deceleration Time (msec)
ICT index (msec)
IRT index (msec)
LV ejection time index (msec)
IMP

Abbreviations: see table 2
Statistics: *p < 0.05, *p < 0.001, *


54 7
31 10
23 7
43 4
112 14
101 10
11.6 2.1
1456 288
36 7
83 22
56 17
1.9 0.8
102 7
296 54
12.5 2.0
151 34
57 34
61 26
204 18
0.58 0.15


52 8
25 5*
27 7*
52 8*
118 17
105 12
8.6 2.7*
1889 146*
33 8
82 15
59 14
1.7 0.7
102 7
340 42**
14.1 2.4*
149 31
23 19***
58 19
194 19
0.42 0.13*


*p < 0.001 vs Paced LV Dysfunction


Abbreviations: see table I; A = peak atrial systolic velocity; DFP =
diastolic filling period; DVI = diastolic velocity integral; E = peak rapid
filling velocity; MAP = mean arterial pressure.
Statistics: *P < 0.05, **p < 0.01, ***p < 0.001 vs Paced LV Dysfunction


0.4- P .0007

0.3 -

0.2 -

0.1 ---
LV Dys LV Dys-Dob
Stage

Figure 2
The effect of dobutamine infusion on IMP with chronic LV
dysfunction: The IMP is plotted for each dog (y axis) at paced
LV dysfunction (LV Dys) and following infusion of dob-
utamine (LV Dys-Dob). With dobutamine infusion, each dog
demonstrated a decline in IMP.


Table 4: Hemodynamics, parameters of LV size, transmitral and
transaortic Doppler and IMP at paced LV dysfunction: 8 and 12
weeks post embolization


Paced LV Paced LV
Dysfunction-8 Dysfunction-12
Weeks Weeks


LV End Diastolic Volume (cc)
LV End Systolic Volume (cc)
Stroke Volume (cc)
LV Ejection fraction (%)
LVSP (mm Hg)
MAP (mm Hg)
LVEDP (mm Hg)
Peak +dP/dT (mm Hg/sec)
Tau (msec)
E (cm/s)
A (cm/s)
E/A
Heart rate (beats/min)
DFP (msec)
Deceleration Time (msec)
ICT index (msec)
IRT index (msec)
LV ejection time index (msec)
IMP


Abbreviations: see table 2


54 7
32 12
22 8
43 4
116 13
104 15
S1.3 2.4
1439 289
36 4
78 19
54 9
1.8 0.7
102 7
311 44
151 29
57 25
58 27
201 22
0.58 0.19


55 6
33 9
22 7
42 4
119 21
105 13
11.2 2.0
1451 184
34 8
82 15
56 13
1.8 0.5
102 7
314 46
149 36
54 22
59 19
197 25
0.57 0.17


Page 5 of 8
(page number not for citation purposes)







Cardiovascular Ultrasound 2006, 4:45


LV Dys LV Dys-Dig
Stage


Figure 3
Effect of digoxin on IMP with chronic LV dysfunction. The
IMP is plotted for each dog (y axis) at paced LV dysfunction
(LV Dys) and following infusion of dobutamine (LV Dys-Dig).
With dobutamine infusion, 13 of 14 dogs demonstrated a
decline in IMP.








load dependent based on changes in LVET and isovolumic
indices especially with LV dysfunction as previously
described using a canine model of chronic ischemic LV
dysfunction [9,10]. In this study, we assessed IMP and its
components in this same model of chronic LV dysfunc-
tion utilizing both an intravenous and oral agent that
increases contractility.

Both inotropic agents significantly increased peak +dP/dT
and LV ejection fraction though the effect of digoxin was
smaller. IMP was markedly reduced with dobutamine
infusion with reductions in both ICT and IRT despite a
reduction in LVET. The reduction in ICT was >70% and
due to a combination of prolongation of time to mitral
closure (12 msec) and shortening of time to onset of aor-
tic flow (18 msec). Similarly oral digoxin for 1 month
resulted in a reduction in the IMP due to a 61% reduction
in ICT. Shortening of the ICT was likely related to the pro-
longation of the time to mitral closure (24 msec). With
both agents, LV filling pressures declined and the diastolic
filling period increased suggesting that reductions in total
isovolumic time resulted in greater time for diastolic fill-
ing. With dobutamine, stroke volume increased and relax-
ation improved allowing a greater filling volume to enter
a more relaxed left ventricle with lower resultant filling
pressures. With digoxin, stroke volume also increased and
was associated with a longer diastolic filling period result-
ing in a lower LV filling pressure. This finding with dig-
oxin is intriguing as its use in patients with preserved LV
function (ejection fraction >40%) has been both advo-
cated and questioned [11,21].


p=0.038


http://www.cardiovascularultrasound.com/content/4/1/45

Previous literature

Using a swine model, LaCorte [8] demonstrated that IMP
was related to changes in cardiac output, preload recruita-
ble stroke work, ejection fraction, and LV stiffness with
both normal LV function and following an ischemic
insult. In a pediatric population, dobutamine reduced
IMP and its components with the reduction in ICT being
the predominant change [5]. Broberg [4] demonstrated in
a mouse model of normal LV systolic function that IMP
correlated with peak +dP/dT using dobutamine. Tei [3], in
his original description, noted a significant relation of
ICT, LVET, and IMP to peak +dP/dT, and IRT to peak -dP/
dT in patients with normal LV function and cardiomyop-
athy patients. A systematic evaluation of contractility
requires a model of LV dysfunction in which a positive ino-
trope is administered or a negative inotrope administered
in a model with normal LVfunction.

However, the relationship between contractile alterations
and IMP is less well delineated in the left ventricle with
reduced LV function. Most information regarding the
effects of contractile alterations are based on an acute
ischemic episode from a normal resting LV function [8].
There are a few studies in patients with nonischemic
dilated cardiomyopathy and coronary disease patients
post myocardial infarction in which dobutamine reduced
IMP in patients with contractile reserve but not in patients
who were ischemic [6,7]. Individual IMP component
analysis was performed only by Duncan [7] who noted a
shortening of ICT and a lengthening of LVET in patients
with nonischemic dilated cardiomyopathy and left bun-
dle branch block undergoing dobutamine echocardiogra-
phy. However, a systematic assessment of the influence of
a contractile agent on IMP and its components in a model
of LV dysfunction has not been evaluated. Our study fills
that void and demonstrates that IMP declines with dob-
utamine and digoxin due to a marked reduction in ICT
using a model of mild LV dysfunction. As salutary effects
of digoxin have been demonstrated in several clinical tri-
als with preserved [9] and reduced LV ejection fractions
[11,22], the data in our trial may shed some light on a
potential mechanism of improvement seen in the DIG
trial. Not only did digoxin decrease IMP by virtue of
reducing the ICT, the diastolic filling period lengthened
and LV end diastolic pressure declined.

Limitations
As this is an experimental study, the applicability of these
findings and relation to intact humans is always a limita-
tion. The general anesthesia utilized may influence the
results. However, this anesthesia regimen has been uti-
lized in multiple experimental studies [9,10,12] and has
not reduced LV systolic function. Second, the use of dob-
utamine was always followed by digoxin administration
may have a generated a series effect. However, the acute
effects of dobutamine were evaluated first and the effect of
digoxin was evaluated after oral therapy several weeks
later. Baseline LV systolic and diastolic function parame-
Page 6 of 8
(page number not for citation purposes)








Cardiovascular Ultrasound 2006, 4:45

ters were virtually unchanged in control LV dysfunction
dogs with a similar degree of LV dysfunction at 8 and 12
weeks post embolization. Baseline LV dysfunction may
change over this time in this model but appears to be asso-
ciated with significant (moderate or greater) mitral regur-
gitation [14]. Third, the model of LV dysfunction used to
assess the IMP may not be applicable to all patients with
LV dysfunction. We believe that this model is applicable
as we used a coronary microsphere model of LV dysfunc-
tion which results in diffuse fibrotic changes throughout
the myocardium which bears great similarity to histopath-
ogy seen in diabetic cardiomyopathy [12,23], ischemic
cardiomyopathy, and hypertensive heart disease with LV
dysfunction. Finally, it is not clear that dobutamine or
digoxin might have similar effects on IMP and its compo-
nents with more severe LV dysfunction. As the LV ejection
fraction was <40% (moderate LV dysfunction) in several
animals, and the responses of IMP and ICT were uniform
in most dogs, it might be reasonable to expect that ino-
tropic stimulation with more severe LV dysfunction might
produce similar responses in IMP and ICT. However, spe-
cific evaluation of dogs with varying degrees of induced
LV dysfunction would be required.

Conclusion
Though IMP has been demonstrated to be load dependent
[9,10], it clearly reflects changes in the contractile state.
IMP, as a single parameter indicator describing a com-
bined systolic-diastolic index, may categorize LV function
and predict prognosis post myocardial infarction or with
dilated cardiomyopathy [1-3]. Its prognostic ability may
very well be based on shortening of ICT and lengthening
of LVET [1,2]. The major influence was on ICY in this
study, and ICY has also been demonstrated to decline
with afterload reduction [10]. A secondary finding was the
reduction in LV end diastolic pressure associated with pro-
longation of diastolic filling with both digoxin and dob-
utamine. In particular, digoxin reduced LV end diastolic
pressure to a similar degree as dobutamine but without
affecting LVET and IRT. As the ejection fraction was mildly
depressed secondary to coronary microsphere induced
micro-infarctions and fibrosis [12], it may have direct rel-
evance to patients with both ischemic and hypertensive
etiologies of LV dysfunction. The significance of the effect
of digoxin on the length of the diastolic filling period
needs further investigation in patients with heart failure
and preserved LV function.

In conclusion, the effect of increasing inotropic stimula-
tion in a model of mild chronic canine LV dysfunction
was determined. Increasing inotropy with digoxin and
dobutamine reduced IMP primarily due to ICY shorten-
ing. Dobutamine had the additional effects of IRT and
LVET shortening. Of note, a shortened ICT, increased
diastolic filling period, and reduced LV end diastolic pres-
sure with digoxin may provide insight into its efficacy in
heart failure.


http://www.cardiovascularultrasound.com/content/4/1/45

List of abbreviations
ICT = isovolumic contraction time

IMP = Index of myocardial performance

IRT = isovolumic relaxation

LV = left ventricular

LVET = left ventricular ejection time

Competing interests
The authors) declare that they have no competing inter-
ests.

Authors' contributions
As this is a single author paper, the author designed,
acquired and analyzed the data. The author drafted and
wrote the manuscript.

Acknowledgements
I would like to thank the American Heart Association of Michigan for their
support. I would like to thank Petar Prcevski D.V.M. and Vicki Johnson for
both their invaluable technical assistance in this investigation. Petar Prcevski
D.V.M. assisted during the invasive procedures and supervised the canine
care. Vicki Johnson prepared the canines for the invasive procedures and
assisted in the hemodynamic analysis. Petar Prcevski's salary support was
derived from the Division of Cardiology of Wayne State University. Vicki
Johnson's salary was derived from the Grant-In-Aid support of the Ameri-
can Heart Association of Michigan. Steven Lavine, M.D. salary supportwas
derived from Wayne State University and their Practice Plans. The Ameri-
can Heart Association awarded a Grant-In-Aid upon a meritorious evalua-
tion by the Grant-In-Aid and Research Committee. The American Heart
Association of Michigan played no role in the collection, analysis and inter-
pretation of data. Similarly, the American Heart Association of Michigan did
not participate in the writing of the manuscript or decisions regarding sub-
mission.

References
I. Dujardin KS, Tei C, Yeo TC, Hodge DO, Rossi A, Seward JB: Prog-
nostic value of a Doppler index combining systolic and
diastolic performance in idiopathic dilated cardiomyopathy.
Am Cardiol 1998, 82:1071 -1076.
2. Poulsen SH, Jensen SE, Nielsen JC, Moller JE, Egstrup J: Serial
changes and prognostic implications of a Doppler derived
index of combined left ventricular systolic and diastolic myo-
cardial performance in acute myocardial infarction. AmJ Cor-
diol 2000, 85:19-25.
3. Tei C, Ling LH, Hodge DO, Bailey KR, Oh jK, Rodeheffer RJ, Tajik AJ,
Seward JB: New index of combined systolic and diastolic myo-
cardial performance: A simple and reproducible measure of
cardiac function-a study in normals and dilated cardiomyop-
athy. J Cardiol 1995, 26:357-366.
4. Broberg CS, Pantely GA, Barber BJ, Mack GK, Lee K, Thigpen T, Davis
LE, Sahn D, Hohimer AR: Validation of myocardial performance
index by echocardiography in mice; a noninvasive measure
of left ventricular function. J Am Soc Echocardiogr 2003,
16:814-23.
5. Harada K, Tamura M, Toyono M, Yasuoka : Effect of dobutamine
on a Doppler echocardiographic index of combined systolic
and diastolic performance. Pediatr Cardiol 2003, 23:613-617.
6. Norager B, Husic M, Moller JE, Egstrup K: The myocardial per-
formance index during low dose dobutamine echocardiogra-
phy in control subjects and patients with recent myocardial
infarction: a new index of left ventricular functional reserve?
J Am Soc Echocardiog 2004, 17:732-738.
7. Duncan AM, Francis DP, Henein MY, Gibson DG: Limitation of
cardiac output by total isovolumic time during pharmaco-

Page 7 of 8
(page number not for citation purposes)








http://www.cardiovascularultrasound.com/content/4/1/45


logic stress in patients with dilated cardiomyopathy. Am Coll
Cardiol 2003, 1:121-8.
8. Lacorte JC, Cabreriza SE, Rabkin DG, Printz BF, Coju L, Weinberg A,
Gersony WM, Spotnitz HM: Correlation of the Tei index with
invasive measurements of ventricular function in a porcine
model. J Am Soc Echocardiogr 2003, 16:442-447.
9. Lavine SJ: Index of myocardial performance is afterload
dependent in the normal and abnormal left ventricle. J Am
Soc Echocardiogr 2005, I 8:342-350.
10. Lavine SJ: Effect of heart rate and preload on index of myocar-
dial performance in the normal and abnormal left ventricle.
J Am Soc Echocardiogr 2005, 18:133-14 1.
II. Digitalis Investigation Group: The effect of digoxin on mortality
and morbidity in patients with heart failure. N Englj Med 1997,
336:525-533.
12. Lavine SJ, Held AC, Prcevski P, Johnson V: Experimental model of
global left ventricular dysfunction secondary to left coronary
microembolization. J Am Coll Cardiol 1991, 18:1794-1803.
13. Nagashima Y, Hirao H, Furukawa A, Hoshi K, Akahane M, Tanaka R,
Yamanae Y: Plasma digoxin concentration in dogs with mitral
regurgitation. j Vet Med 2001, 63:1 199-1202.
14. Sabbah HN, Shimoyama HN, Kono T, Gupta RC, Sharov VG, Scicli G,
Levine TB, Goldstein S: Effects on long term monotherapy with
enalapril, metoprolol, and digoxin on the progression of left
ventricular dysfunction and dilatation in dogs with reduced
ejection fraction. Circulation 1994:2852-2859.
15. Weiss jL, Fredrickson JW, Weisfeldt ML: Hemodynamic determi-
nants of the time course of fall in canine left ventricular pres-
sure. j Clin Invest 1976, 58:751-760.
16. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereaux R, Feigen-
baum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, Silverman NH,
Tajik AJ: Recommendations for quantitation of the left ventri-
cle by two-dimensional echocardiography. American Society
of Echocardiography Committee on Standards, Subcommit-
tee on Quantitation of Two-Dimensional Echocardiograms.
J Am Soc Echocardiogr 1989, 2:358-67.
17. Poulsen SH, Jensen SE, Tei C, Seward JB, Egstrup K: Value of the
Doppler index of myocardial performance in the early phase
of acute myocardial infarction. J Am Soc Echocardiogr 2000,
13:723-730.
18. Moller JE, Sondergaard E, Poulsen SH, Egstrup K: the Doppler
echocardiographic myocardial performance index predicts
left ventricular dilatation and cardiac death after myocardial
infarction. Cardiology 2001, 95:105- II I.
19. Tei C, Dujiardin KS, Hodge DO, Kyle RA, Tajik AJ, Seward JB: Dop-
pler index combining systolic and diastolic myocardial per-
formance: clinical value in amyloidosis. J Am Coll Cardiol 1996,
28:658-664.
20. Yeo TC, Dujiardin KS, Teic Mahoney DW, McGoon MD, Seward J:
Value of a Doppler derived MPI combining systolic and
diastolic time intervals in predicting outcome in primary pul-
monary hypertension. Am] Cardiol 1998, 81:1 157-1161.
21. Aronow WS: Epidemiology, pathophysiology, prognosis, and
treatment of systolic and diastolic heart failure in elderly
patients. Heart Dis 2003, 5:279-294.
22. Heck I, Luderitz B, Muller HM, Esser H: A comparison of Capto-
pril and digoxin in the treatment of patients with mild to
moderate chronic congestive heart failure. Clin Ther 1995,
17:270-279.
23. Factor SM, Okun EM, Minase T: Capillary microaneurysms in the
human diabetic heart. N Englj Med 1980, 302:384-388. Publish with BioMed Central and every
scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical research in our lifetime."
Sir Paul Nurse, Cancer Research UK
Your research papers will be:
available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours you keep the copyright

Submit your manuscript here: BioMedcentral
http://www.biomedcentral.com/info/publishingadv.asp -


Page 8 of 8
(page number not for citation purposes)


Cardiovascular Ultrasound 2006, 4:45




University of Florida Home Page
© 2004 - 2010 University of Florida George A. Smathers Libraries.
All rights reserved.

Acceptable Use, Copyright, and Disclaimer Statement
Last updated October 10, 2010 - - mvs