Improvement of afterload mismatch of left atrial buster pump function with positive inotropic agent

Article (PDF Available)inJournal of the American College of Cardiology 37(1):270-7 · January 2001with10 Reads
DOI: 10.1016/S0735-1097(00)01060-3 · Source: PubMed
Abstract
The objective of this study was to examine the hypothesis that a positive inotropic agent improves left ventricular (LV) filling during left atrial (LA) contraction in the presence of markedly elevated LV filling pressure. In patients with old myocardial infarction (MI), an increase in the operational LV chamber stiffness reduces LV filling during the LA contraction, resulting from an "afterload mismatch" of the LA booster pump function. We investigated the effect of dobutamine infusion (3 microg/kg/min) on the LA pump function in the presence of elevated LV filling pressure induced by aortic constriction (Aoc) during acute MI in 10 dogs. Transmitral flow velocity was determined by transesophageal echocardiography, LV pressure by a micromanometer and LV volume by a conductance catheter. We measured the early (E) and late (A) diastolic peak transmitral flow velocities (cm/s) and LV chamber stiffness (deltaP/deltaV: mm Hg/ml; where deltaP is developed pressure and deltaV is the absolute filling volume during LA contraction). When the deltaP/deltaV was increased by Aoc during MI (from 1.1 +/- 0.8 to 3.1 +/- 2.6 mm Hg/ml, p < 0.01), A decreased significantly (from 30 +/- 5 to 22 +/- 8 cm/s, p < 0.01), and the ratio of E to A increased (from 1.0 +/- 0.3 to 1.4 +/- 0.8, p < 0.05) compared with MI without Aoc, showing the pseudonormal transmitral flow pattern, the so called "LA afterload mismatch." Dobutamine under this condition significantly reduced the deltaP/deltaV (to 1.7 +/- 1.2 mm Hg/ml, p < 0.05), resulting in an increase in A (to 31 +/- 8 cm/s, p < 0.01) and a decrease in E/A (to 1.0 +/- 0.3, p < 0.05), and the transmitral flow became a prolonged relaxation pattern as in MI without Aoc in all dogs. There was an inverse correlation between the deltaP/deltaV and the time-velocity integral of A (r = -0.70, p < 0.01). Dobutamine improved the afterload mismatch of the LA booster pump function. This effect may have been due to the reduction in LV operational chamber stiffness, resulting in an increase in the LA forward ejection into the LV.
Improvement of Afterload Mismatch of Left Atrial
Booster Pump Function With Positive Inotropic Agent
Hisanori Sakai, MD, Hideki Kunichika, MD, Kazuya Murata, MD, Kohzaburo Seki, MD,
Kazuhiro Katayama, MD, Takafumi Hiro, MD, Toshiro Miura, MD, Masunori Matsuzaki, MD, FACC
Yamaguchi, Japan
OBJECTIVES The objective of this study was to examine the hypothesis that a positive inotropic agent
improves left ventricular (LV) filling during left atrial (LA) contraction in the presence of
markedly elevated LV filling pressure.
BACKGROUND In patients with old myocardial infarction (MI), an increase in the operational LV chamber
stiffness reduces LV filling during the LA contraction, resulting from an “afterload mismatch”
of the LA booster pump function.
METHODS We investigated the effect of dobutamine infusion (3
g/kg/min) on the LA pump function
in the presence of elevated LV filling pressure induced by aortic constriction (Aoc) during
acute MI in 10 dogs. Transmitral flow velocity was determined by transesophageal
echocardiography, LV pressure by a micromanometer and LV volume by a conductance
catheter. We measured the early (E) and late (A) diastolic peak transmitral flow velocities
(cm/s) and LV chamber stiffness (P/V: mm Hg/ml; where P is developed pressure and
V is the absolute filling volume during LA contraction).
RESULTS When the P/V was increased by Aoc during MI (from 1.1 0.8 to 3.1 2.6 mm Hg/ml,
p 0.01), A decreased significantly (from 30 5to228 cm/s, p 0.01), and the ratio
of E to A increased (from 1.0 0.3 to 1.4 0.8, p 0.05) compared with MI without Aoc,
showing the pseudonormal transmitral flow pattern, the so called “LA afterload mismatch.”
Dobutamine under this condition significantly reduced the P/V (to 1.7 1.2 mm Hg/ml,
p 0.05), resulting in an increase in A (to 31 8 cm/s, p 0.01) and a decrease in E/A
(to 1.0 0.3, p 0.05), and the transmitral flow became a prolonged relaxation pattern as
in MI without Aoc in all dogs. There was an inverse correlation between the P/V and the
time-velocity integral of A (r ⫽⫺0.70, p 0.01).
CONCLUSIONS Dobutamine improved the afterload mismatch of the LA booster pump function. This effect
may have been due to the reduction in LV operational chamber stiffness, resulting in an
increase in the LA forward ejection into the LV. (J Am Coll Cardiol 2001;37:270–7) © 2001
by the American College of Cardiology
Atrial booster pump function plays an important role in the
left ventricular (LV) filling, particularly in patients with
early LV diastolic dysfunction in whom an increase in left
atrial (LA) contraction results in the maintenance of LV
filling and a normal cardiac output (1,2). The mitral flow
velocity pattern, as determined by pulsed Doppler echocar-
diography in such patients with early diastolic dysfunction,
reveals a decreased early diastolic velocity (E wave) and an
increased late diastolic velocity (A wave). However, when
the severity of LV diastolic dysfunction increases, a different
pattern of LV diastolic filling is observed, which is called
“pseudonormal,” indicating a reversal of the abnormal ratio
of mitral E and A wave velocities (2,3). When this occurs
the increased LA contribution to LV filling as a compen-
satory mechanism in response to reduced early filling is lost,
and a decrease in the mitral A wave is observed. An optimal
therapy for these patients would be a medication that would
increase the reduced efficiency of LA booster pump function
in the presence of diastolic dysfunction.
The data on LA pump function, particularly in relation to
elevated LV end-diastolic pressure have been reported from
the labs of Hoit, Kawamura and Toutouzas (46). We have
previously demonstrated that, in patients with old myocar-
dial infarction (MI), the increase in the operational LV
chamber stiffness at end-diastole induced by an acute
pressure load significantly reduced LV filling during LA
contraction, resulting from an “afterload mismatch” of the
LA booster pump function (7).
It was hypothesized that a reduction in LV chamber
stiffness produced by a positive inotropic agent improves LV
filling during LA contraction in the presence of markedly
elevated LV filling pressure. The aim of this study was to
examine the effects of dobutamine (DOB) on LA booster
pump function in dogs with pseudonormalization of the
transmitral flow velocity pattern due to an afterload
mismatch between the LA and the LV during atrial
contraction.
METHODS
Animal preparation and data collection. Ten adult mon-
grel dogs weighing between 9 and 17 kg (mean 12.4 kg)
From the Second Department of Internal Medicine, Yamaguchi University School
of Medicine, Yamaguchi, Japan. Supported, in part, by research grants 07670785
from the Ministry of Education, Science and Culture of Japan. Presented, in part, at
the 43rd Annual Scientific Sessions of the American College of Cardiology, Atlanta,
Georgia, 1994.
Manuscript received February 28, 2000; revised manuscript received July 24, 2000,
accepted September 11, 2000.
Journal of the American College of Cardiology Vol. 37, No. 1, 2001
© 2001 by the American College of Cardiology ISSN 0735-1097/01/$20.00
Published by Elsevier Science Inc. PII S0735-1097(00)01060-3
were sedated with morphine sulfate (3 mg/kg subcutaneous)
30 min before the induction of general anesthesia with
-chloralose (30 mg/kg intravenous). They were ventilated
with a Harvard respirator; the concentration of inspired
oxygen and the ventilation rate were adjusted to maintain
blood gases within the physiologic range. The chest was
opened laterally through the fifth left intercostal space, and
the pericardium was incised parallel to the phrenic nerve
and opened. The heart was placed in a pericardial cradle.
The sinus node was crushed, and a pacing wire was sutured
on the LA appendage to keep the heart rate constant at 100
beats/min.
One micromanometer-tipped catheter (model PC-484A,
Millar Instruments, Houston, Texas) was placed in LA
through an incision in the LA appendage, and another was
placed in the LV across the aortic valve via the left carotid
artery. To ensure the accuracy of pressure measurements,
the micromanometers and a fluid-filled transducer (Statham
P23ID, Statham Instruments, Oxnard, California) were
balanced, calibrated with a mercury manometer and ad-
justed for equal gain before insertion. The fluid-filled
transducer, which was positioned at the midthoracic level,
was balanced to atmospheric pressure to serve as the
pressure baseline. The zero shift during the procedure was
adjusted by comparing pressures, measured simultaneously
by the fluid-filled lumens connected to the fluid-filled
transducer. We confirmed that LV and LA diastolic pres-
sures were identical during late diastasis. At the end of the
experiment, the catheters were withdrawn and exposed to
air to confirm the accurate registration of zero pressure.
To obtain the LV volume, an 8-pole electrode conduc-
tance catheter (Leycom, Netherlands) was introduced into
the LV from the apex guided by two-dimensional trans-
esophageal echocardiography and positioned along the long
axis with the distal tip beneath the subaortic valve. The
catheter was connected to a stimulator/signal processor
(Sigma 5, Leycom, Netherlands). For catheter placement
we examined each segmental pressure-volume loop to con-
firm that all segments were intracavitary and displayed a
normal counterclockwise pressure-volume resurgence. The
conductance catheter technique, which is based on the fact
that changes in blood conductance in the LV are propor-
tional to changes in LV volume, has been previously
described (8). A fluid-filled catheter was placed in the
pulmonary artery to calibrate the volume signal. Calibration
was performed by the hypertonic saline technique (8), and
saline was rapidly injected into the pulmonary artery at the
end of expiration.
A pair of ultrasonic crystals (3-MHz, 2.5 mm in diame-
ter) were attached face-to-face on the surface of the LA
anterior and posterior walls to measure LA diameter.
The transmitral flow velocity was measured by transesoph-
ageal pulsed Doppler echocardiography using an ultrasound
system (Aloka, Japan) with a 5-MHz Doppler transducer.
The sample volume was placed between the mitral leaflets in
the transesophageal four-chamber view.
Finally, one occluder was positioned around the descend-
ing aorta a few centimeters above the level of the diaphragm
for the increase of afterload, and another occluder was
placed around the proximal portion of the left anterior
descending coronary artery to produce acute regional MI.
Experimental protocol. Pseudonormalization of the trans-
mitral flow velocity pattern was produced by aortic constric-
tion (Aoc) using the occluder during acute MI. The
protocol consisted of three stages. First, data were acquired
at baseline. Second, acute regional MI was produced by
occluding the left anterior descending coronary artery.
Recordings were made before and after Aoc about 15 min
after occlusion to obtain a steady state. Finally, a DOB
infusion (3
g/kg/min) was initiated during MI. After a
stable hemodynamic state was confirmed, recordings were
again obtained with Aoc. The Aoc was carefully performed
to increase the LV peak systolic pressure to the identical
levels in each stage.
Assessment of the pulmonary venous (PV) flow. To
further examine the relation between transmitral flow and
PV flow in the presence of markedly reduced LV filling at
LA contraction, simultaneous recordings of PV flow vol-
umes with transmitral flow velocity were made by an
ultrasonic flowmeter (T106, Transonic Systems Inc, New
York) in six additional dogs. The flowmeter was carefully
placed around the upper left PV to avoid interfering with
the venous flow.
Analysis of data. Micromanometric, sonomicrometric and
conductance catheter signals were obtained for 15 s and
digitized at 200 Hz using an on-line A to D conversion with
custom software (The Codas, DATAQ Inc., Akron, Ohio)
on a 32-bit microcomputer system (IBM PC/AT) during
the end-expiratory portion of the respiratory cycle. The
transmitral flow velocity was simultaneously recorded on
paper at a speed of 100 mm/s. The average of measurements
obtained from at least five consecutive beats was deter-
mined.
The following measurements and calculations were per-
formed: peak LV pressure, LV end-diastolic pressure, LA
end-diastolic pressure, peak positive and negative LV dP/dt
and the time constant of LV isovolumetric pressure decay
(tau). Tau was computed as the negative reciprocal of the
linear regression of the natural logarithm of pressure versus
Abbreviations and Acronyms
A late diastolic transmitral flow velocity
Aoc aortic constriction
DOB dobutamine
E early diastolic transmitral flow velocity
LA left atrium/left atrial
LV left ventricle/left ventricular
MI myocardial ischemia/myocardial infarction
PV pulmonary vein/pulmonary venous
() with
() without
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Improvement of LA Afterload Mismatch by DOB Infusion
time, and the LV end-diastole was determined at the time
when the LV dP/dt commenced its rapid upstroke as
previously reported (9). The cardiac output and the diastolic
LV pressure-volume relation were determined from record-
ings of LV volume. The LV diastolic chamber stiffness
constant was obtained by fitting the diastolic LV pressure-
volume data to an exponential curve equation P Ae
kV
,
where P is LV pressure, the constant A is the y axis
intercept, e is the base of the natural logarithm, k is the
chamber stiffness constant, and V is LV volume. The LV
end-diastolic operational chamber stiffness was estimated as
the ratio of developed pressure to the absolute filling volume
during LA contraction. The onset of atrial contraction was
picked by LA dimensional change.
The LA diameter before atrial contraction and the
percent of LA systolic shortening were determined from the
LA dimension. The percent of LA systolic shortening was
calculated as the ratio of the change in the LA diameter
during LA contraction to the LA diameter at the beginning
of LA contraction.
The following measurements were obtained from the
transmitral flow recordings: early diastolic peak flow velocity
(E), late diastolic peak flow velocity (A), time-velocity
integral of E and A and the ratio of E to A (E/A). In
addition, peak (minimum) PV flow volumes during LA
contraction were obtained. In experimental open-chest
dogs, different from clinical findings, the PV flow during
LA contraction usually moves into the LA and is not ejected
from the LA backward into the PVs (10). When the
backward flow volume occurred during LA contraction, it
was represented by a negative value in our data process.
Statistical analysis. Data are expressed as the mean
standard deviation. One-way analysis of variance for re-
peated measures was used to test for significant differences
between data obtained at four states: baseline, MI without
and with Aoc and DOB infusion during MI with Aoc.
Fisher PLSD was used for multiple comparisons within
analysis of variance. Relationship between the time-velocity
integral of late diastolic transmitral flow and LV operational
chamber stiffness, which was obtained from all sampled
data, was assessed with linear regression analysis. A p value
0.05 was considered statistically significant.
RESULTS
Mean steady-state hemodynamic and dimension data are
summarized in Table 1. Peak LV pressure was not changed
at baseline, at acute MI or at DOB infusion during acute
MI, whereas the Aoc resulted in a similar increase in peak
LV pressure by about 55 mm Hg at each state. There were
statistically no significant differences in the percent of LA
systolic shortening in any condition, although the changes
of LA diameter were observed.
Transmitral flow. Representative transmitral flow wave
forms are shown in Figure 1. The Aoc during MI induced
a significant reduction of A, indicating the development of
pseudonormalization of transmitral flow velocity pattern.
However, by DOB infusion during Aoc under MI, A was
increased, resulting in an improvement of the LV filling
during LA contraction.
Mean changes in transmitral flow velocities are provided
in Table 2. Constriction of the aorta during acute MI
significantly reduced A and pseudonormalized the E/A.
The infusion of DOB under this condition increased A,
resulting in a decreased E/A. Using the time-velocity
integral of E and A, the identical changes to velocity
changes were observed in all the stages.
The relations between transmitral flow and PV flow.
Figure 2 shows representative simultaneous recordings of
the transmitral and PV flows and recordings of LV and LA
pressures during acute MI before (left) and after (mid) Aoc
and with dobutamine infusion (right). In the presence of a
Table 1. Hemodynamic and Dimension Data
Baseline
Acute MI
Aoc() Aoc()
Aoc()
DOB
HR (beats/min) 104 4 102 6 102 7 107 14
LVP (mm Hg) 114 15 108 17 166 24*‡ 173 26*‡
LVEDP (mm Hg) 7 2114* 18 6*‡ 14 4*§
Peak LV dP/dt (mm Hg/s) 2,275 662 1,838 549 2,064 542 2,674 858‡¶
dP/dt (mm Hg/s) 2,086 482 1,702 497† 1,845 399 2,222 504§¶
Tau (ms) 30 73810† 49 11*§ 40 11†¶
LAP (mm Hg) 9 4113144*§ 13 5*
LAD (mm) 29 4303* 31 3*‡ 30 3*§
LASS (%) 6 3736474
CO (L/min) 1.6 0.6 1.4 0.3 0.9 0.1*§ 1.4 0.3¶
K (ml
1
) 0.10 0.09 0.10 0.12 0.12 0.07 0.09 0.05
y axis intercept (mm Hg) 0.44 1.64 0.41 2.07 0.88 1.18 0.07 1.05
*p 0.01; †p 0.05 vs. baseline; ‡p 0.01; §p 0.05 vs. acute MI Aoc(); p 0.01; ¶p 0.05 vs. acute MI Aoc().
Aoc aortic constriction; CO cardiac output; DOB dobutamine; HR heart rate; K left ventricular stiffness
constant; LAD left atrial diameter before atrial contraction; LAP left atrial end-diastolic pressure; LASS % left atrial
systolic shortening; LV left ventricular; LVEDP left ventricular end-diastolic pressure; LVP peak left ventricular
pressure; LV dP/dt positive and negative first derivative of left ventricular pressure; MI myocardial ischemia; Tau time
constant of left ventricular relaxation. (Values are the mean SD).
272 Sakai
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Improvement of LA Afterload Mismatch by DOB Infusion
January 2001:270 –7
pseudonormal LV diastolic filling pattern induced by Aoc,
the PV reverse flow at atrial systole was significantly
increased (Fig. 2, mid). The infusion of DOB completely
eliminated the PV reverse flow, accompanied by a signifi-
cant increase in the late diastolic transmitral flow (Fig. 2,
right). Comparative data of the peak (minimum) PV flow
volume at LA contraction in each state are shown in Figure
3. With Aoc during MI, the forward PV flow at atrial
systole was replaced by a significant reverse flow into the PV
(from 16.7 12.0 to 52.8 38.1 ml/min, p 0.01).
However, PV flow was normalized to change from the
backward flow to forward flow by DOB infusion (to 12.2
19.4 ml/min, p 0.01).
Changes in the diastolic LV pressure-volume relation
and LV chamber stiffness. Figure 4 (top) displays repre-
sentative diastolic LV pressure-volume relations at baseline,
during acute MI and during acute MI with DOB infusion
all before Aoc. Dobutamine infusion caused the diastolic
LV pressure-volume relation to shift to the left and down-
ward compared with that seen in MI without DOB. The
LV chamber stiffness constant and the y axis intercept were
not changed in any state (Table 1). Linear stiffness analysis
was performed, and Figure 4 (bottom) shows changes in LV
chamber stiffness at each state. The LV operational chamber
stiffness was significantly increased by Aoc during MI from
1.1 0.8 to 3.1 2.6 mm Hg/ml (p 0.01). The infusion
of DOB under this condition significantly reduced the
increased LV chamber stiffness to 1.7 1.2 mm Hg/ml
(p 0.05).
Relationship between the time-velocity integral of the
late diastolic transmitral flow and LV chamber stiffness.
There was a significant inverse correlation between the
time-velocity integral of the late diastolic transmitral flow
and LV chamber stiffness (Fig. 5).
DISCUSSION
Transmitral and PV flow dynamics in the presence of LA
afterload mismatch between LA and LV during atrial
contraction. Figure 2 (upper mid panel) shows the simul-
taneous recordings of transmitral and PV flows in the
presence of a pseudonormal transmitral flow pattern. We
demonstrated that, although the percentage of LA systolic
shortening was not changed by Aoc during acute MI, LV
filling during LA contraction was significantly reduced.
This resulted from an LA afterload mismatch, which was
closely linked to an increase in the volume of blood ejected
from the atrium backward into the PVs. The LA afterload
mismatch concept in relation to LV stiffness was already
reported (5). The new finding in this study, which differs
from the previous report, is that the constant LA systolic
performance was observed during the LA afterload mis-
match accompanied by the prominent backward flow from
Figure 1. Transmitral flow velocity. Representative transmitral flow waveforms at baseline and during acute myocardial ischemia (MI) and acute MI with
dobutamine (DOB). Aortic constriction (Aoc) during acute MI significantly reduced the late diastolic peak flow velocity, indicating pseudonormalization
of the transmitral flow. Dobutamine infusion during acute MI with Aoc increased the late diastolic peak flow velocity, resulting in an improvement in left
ventricular (LV) filling during left atrial (LA) contraction. ECG electrocardiogram.
Table 2. Mean Changes in Transmitral Flow Velocities
Baseline
Acute MI
Aoc() Aoc()
Aoc()
DOB
A (cm/s) 29 7305228*‡ 31 8
E (cm/s) 43 7317* 26 8*§ 30 9*
E/A 1.5 0.2 1.0 0.3† 1.4 0.8§ 1.0 0.3†¶
Time-velocity integral of A (cm) 1.7 0.4 1.8 0.3 1.1 0.5*‡ 1.8 0.5
Time-velocity integral of E (cm) 3.3 0.5 2.2 0.6* 1.6 0.6*§ 2.0 0.8*
A late diastolic peak velocity; Aoc aortic constriction; DOB dobutamine; E early diastolic peak velocity; MI
myocardial ischemia (values are the mean SD).
*p 0.01; †p 0.05 vs. baseline; ‡p 0.01; §p 0.05 vs. acute MI Aoc(); p 0.01; ¶p 0.05 vs. acute MI Aoc().
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Improvement of LA Afterload Mismatch by DOB Infusion
the LA to the PVs. This is the main feature of LA afterload
mismatch in the present model.
With atrial contraction, blood is ejected from the LA into
the LV determined by the positive transmitral pressure
gradient (11) and also backward into the PVs. The flow in
each direction is determined by the pressure gradient from
the PVs to the LV, which is likely influenced by LA systolic
function, LA systolic timing (12,13) and compliance of LA
and LV.
Nishimura et al. (13) indicated that there was a detri-
mental effect of dual-chamber pacing for patients with
hypertrophic cardiomyopathy on LV diastolic function,
particularly at the short atrioventricular interval pacing.
They observed that an increase in E/A ratio and a decrease
in duration of transmitral A wave in the short atrioventric-
ular intervals (due to inadequate time for LA contraction to
fill the LV) was fully associated with an increase in mean
LA pressure caused by a higher residual LA volume at
mitral valve closure. This is due to LA systolic timing.
Under normal circumstances, increases in pressure in the
LA and the LV during atrial contraction are approximately
equal, and the transmitral flow exceeds the reverse flow into
the PVs. However, with reduced LV compliance and
elevated filling pressures, as shown in Figure 2 (lower mid
panel), the pressure increase is larger and more rapid in the
LV than it is in the LA (7), resulting in a reduced
transmitral flow. Thus, atrial contraction results in a marked
reversal of flow into the PVs. Because of this increased
reverse flow, the efficiency of LA booster pump function
was significantly reduced during LA afterload mismatch for
the same degree of atrial systolic shortening. On the other
hand, an LV afterload mismatch can be induced by pressure
loading under inadequate venous return (14), even at a
stable level of myocardial contractility. The LA afterload
mismatch may also occur even at a stable level of LA pump
function operating before the descending limb of LA
performance curve (15) because the backward flow into the
PVs exceeds transmitral flow during atrial contraction.
Figure 2 (upper mid panel) shows that these PV flow
patterns differentiate between a high E/A ratio associated
Figure 2. The relation between transmitral flow and PV venous flow and changes of LA and LV pressures with or without DOB. Representative
simultaneous recordings of the transmitral flow velocity and PV flow volume and tracings of LV pressure and magnified LV and LA pressures (arrows in
right lower panel). With Aoc during MI, the pressure increase is larger and more rapid in the LV than it is in the LA at atrial systole (lower mid panel),
resulting in a reduced late diastolic transmitral flow velocity and an increased PV reverse flow volume (upper mid panel). Thus, in the presence of an LA
afterload mismatch, a substantial blood volume was ejected from the LA backward into the PV with atrial contraction. Dobutamine infusion markedly
corrected this mismatch (upper right panel). Aoc aortic constriction; DOB dobutamine infusion; LA left atrial; LV left ventricular; MI
myocardial ischemia; PV pulmonary vein.
Figure 3. Changes in peak (minimum) PV flow volume during atrial
contraction at each stage. The backward flow into the PV is represented by
a negative value. Data are the mean standard deviation. Aoc aortic
constriction; DOB dobutamine infusion; MI myocardial infarction or
ischemia; PV pulmonary vein.
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with normal diastolic function characterized by a normal PV
flow pattern and a high E/A ratio due to pseudonormaliza-
tion associated with reduced LV compliance characterized
by a PV flow pattern with a marked atrial flow reversal (2,3).
Rossvoll et al. (16) reported that when the LV filling
pressure was markedly increased, the pressure increase was
greater and more rapid in the LV than it was in the LA,
resulting in a short duration of the positive transmitral
pressure gradient, and that the amount and duration of flow
in each direction was determined by the transmitral and
atriovenous pressure gradients. They observed a difference
in the durations of PV and transmitral flow velocities during
atrial contraction, which indicates an exaggerated increase
in LV late diastolic pressure, caused by the increased
duration of flow backward into the PVs and the decreased
duration of transmitral flow. The present findings were
consistent with their findings.
Mechanism of the effect of DOB on the afterload
mismatch of atrial booster pump function. To explain the
improvement of LA afterload mismatch by DOB, at least two
possible mechanisms should be considered. Left atrial systolic
function may be increased by DOB or, if DOB improves LV
compliance, LA afterload during LA contraction would be
reduced. In this study, the percent of LA systolic shortening
was not significantly changed throughout the study even by
DOB infusion. Thus, a significant alteration in LA booster
pump function seems unlikely to be induced by an augmenta-
tion of LA contractility during DOB infusion.
Afterload on the LA is primarily determined by LV
chamber stiffness and LV pressure just before the onset of
LA contraction. When diastolic pressure is elevated, the
operational chamber stiffness of the LV is increased because
it functions on a steeper portion of its pressure-volume
curve. We demonstrated that DOB infusion caused the
diastolic LV pressure-volume relation during acute MI to
shift to the left and downward. We monitored LV chamber
stiffness, calculated as the ratio of developed pressure to the
absolute filling volume during LA contraction, throughout
the experiment. Dobutamine significantly reduced the
markedly increased LV chamber stiffness during LA after-
load mismatch, whereas no significant changes in the LV
chamber stiffness constant and the y axis intercept were
observed in any state of this study. The change in the
pressure-volume relation may not be due to a change in
myocardial compliance, but rather to a shift in the position
of the pressure-volume curve on the diastolic LV pressure-
volume relationship. These findings suggest that DOB
reduced the afterload on LA. Carroll et al. (17) reported
that DOB reduced the LV diastolic pressure without
significant changes in the LV chamber stiffness constant and
caused a left-downward shift in the same diastolic pressure-
diameter relation (due to the reduced end-systolic chamber
size) and reduced the minimum diastolic pressure in pa-
tients with congestive cardiomyopathy. Other investigators
have reported similar findings (18–21). Based on these data,
we propose that the DOB-induced correction of LA after-
load mismatch did not result from an alteration of LA
systolic function but rather from an improvement in the
efficiency of the LA booster pump function by a reduction
of the afterload on LA.
Figure 5. Relationship between the time-velocity integral of the A and LV
operational chamber stiffness for all the data points in this study. A late
diastolic transmitral flow velocity; LV left ventricle.
Figure 4. Changes in diastolic LVP-volume relations and changes in LV
chamber stiffness at each stage. Top: Representative diastolic LVP-volume
relations at baseline, during MI and during MI with DOB all without Aoc.
Bottom: Changes in LV chamber stiffness at baseline, during MI and
during MI with DOB, with or without Aoc. Data are the mean SD.
Aoc aortic constriction; DOB dobutamine infusion; LV left
ventricle; LVP left ventricular pressure; MI myocardial ischemia.
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Improvement of LA Afterload Mismatch by DOB Infusion
Relationship between the time-velocity integral of late
diastolic transmitral flow and LV operational chamber
stiffness. In situations in which LV compliance is markedly
decreased, such as constrictive pericarditis and restrictive
cardiomyopathy, most abnormal LV filling pattern, so called
“restricted” LV filling pattern, has been observed and is
characterized by a tall, narrow early filling wave in associa-
tion with a high-peak velocity and a shortened deceleration
time caused by an abnormally rapid increase in early
diastolic LV pressure and a small atrial filling wave (3,22).
Myocardial ischemia is associated with an immediate de-
crease in myocardial compliance (23–25). So, it is expected
that the filling pattern observed in this study in dogs with
afterloading induced by Aoc during MI, which was attrib-
uted to much lower LV chamber compliance than that
solely due to MI, will resemble the filling behavior seen in
the markedly elevated LV filling pressure associated with
the “restricted” LV filling pattern. This finding is in
agreement with a previous report from our group (7). We
previously demonstrated that, in patients with old MI, the
increase in LV operational chamber stiffness induced by
acute pressure load during angiotensin infusion significantly
reduced LV filling during atrial contraction, resulting from
an afterload mismatch of LA booster pump function, and
that there was an inverse correlation between LV filling
volume at atrial contraction and LV chamber stiffness. In
this study a significant inverse correlation between the
time-velocity integral of the late diastolic transmitral flow
and the LV operational chamber stiffness was observed
under the same percentage of LA systolic shortening. This
relationship suggests that the LV operational chamber
stiffness plays an important role in affecting the efficiency of
LA booster pump function.
Study limitations. In this study measurements of LA
volume were only based on the anteroposterior dimension.
This is a limitation of the study because dimensional
changes during atrial contraction may be dissimilar in
different dimensions (26). However, this limitation might
be counterbalanced by identical methodology during mea-
surements on the basis of percentage of shortening ratio in
different phases of the protocol.
Conclusions. Dobutamine improved the afterload mis-
match of LA booster pump function associated with
pseudonormalization of the transmitral flow velocity pattern
during acute MI with afterloading. This effect may have
been due to a reduction in LV operational chamber stiffness
at late diastole (reduction of LA afterload) induced by
DOB, leading to an increase in the LA forward ejection into
the LV associated with a decrease in backward flow volume
into the PVs during atrial contraction.
Reprint requests and correspondence: Dr. Masunori Matsuzaki,
Second Department of Internal Medicine, Yamaguchi University
School of Medicine, 1-1-1 Minamikogushi, Ube, 755-8505,
Yamaguchi, Japan.
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