Vol. 279, Issue 3, H1264-H1273, September 2000
Efficiency of energy transfer, but not external work, is
maximized in stunned myocardium
Serge A. I. P.
Trines,
Cornelis J.
Slager,
Joost
Van der Moer,
Pieter D.
Verdouw, and
Rob
Krams
Experimental Cardiology and Hemodynamics Laboratory,
Thoraxcenter, Erasmus University Rotterdam, 3000 DR Rotterdam,
The Netherlands
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ABSTRACT |
There is no evidence regarding the effect
of stunning on maximization of regional myocardial external work (EW)
or efficiency of energy transfer (EET) in relation to regional
afterload (end-systolic stress, 
es). To that end, we
studied these relationships in both the left anterior descending
coronary artery (LADCA) and left circumflex coronary artery regions in
anesthetized, open-chest pigs before and after LADCA stunning. In
normal myocardium, EET vs. es was maximal at 75.4 (69.7-81.0)%, whereas EW vs. es was submaximal at
12.0 (6.61-17.3) × 102 J/m3.
Increasing es increased EW by 18 (10-27)%. Regional myocardial stunning decreased EET
(27%) and EW (36%) and caused the myocardium to operate both at
maximal EW (EWmax) and at maximal EET (EETmax). EET and EW became also more sensitive to changes in es.
In the nonstunned region the situation remained unchanged. Combining the data from before and after stunning, both EWmax and
EETmax displayed a positive relationship with
contractility. In conclusion, the normal regional myocardium operated
at maximal EET rather than at maximal EW. Therefore, additional EW
could be recruited by increasing regional afterload. After myocardial
stunning, the myocardium operated at both maximal EW and maximal EET,
at the cost of increased afterload sensitivity. Contractility was a
major determinant of this shift.
stunning; pig; contractility; regional energy
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INTRODUCTION |
LEFT VENTRICULAR EXTERNAL
WORK (EW) and left ventricular efficiency of energy transfer
(EET) have been shown to depend on a complex interplay of afterload,
preload, and contractility (20). The individual
contribution of these factors to EW and EET may be quantified using the
time-varying elastance concept (23). According to this
concept, the left ventricular elastance, measured by the instantaneous
ratio of pressure over volume (minus the extrapolated volume at zero
pressure), changes during a cardiac cycle from a minimal end-diastolic
value to a maximal end-systolic value. The latter value (end-systolic
elastance, Ees) is a measure of contractility
(23). The area bounded by the end-diastolic and
end-systolic pressure-volume relationships, and the systolic trajectory
of the pressure-volume loop is a measure of total left ventricular
work, whereas the area within the pressure-volume loop is a measure of
left ventricular EW. Left ventricular EET is defined as the ratio of EW
over total work.
Several studies have addressed the relationship of power, EW, or EET
vs. afterload and have found a maximum in power (20, 25) but not in EET (4). Until now, these
relationships have been derived for global heart function, whereas most
of the cardiac pathophysiology is associated with regional dysfunction
(27). However, to study the energy-afterload relationships
during regional dysfunction, it is necessary to apply the physiological
concepts on a regional basis. To the best of our knowledge, it is
presently unknown whether relationships involving EW, EET, and
afterload derived for global hearts are applicable to regional
myocardium. Hence, the first aim of the present study was to evaluate
in open-chest anesthetized pigs whether maxima in EW and EET, as found
in global hearts, are present in regional myocardium in open-chest
pigs. As a measure for afterload, we applied regional end-systolic
stress (es), as arterial properties, e.g., effective
arterial elastance, cannot constitute afterload for regional myocardium.
Impairment of global left ventricular function causes the ventricle to
deviate from the optimal situation (11, 21). In earlier
work, we have shown that, after myocardial stunning, both regional EW
and regional EET decreased more than before stunning, when end-systolic
pressure was increased (9). In view of the above-mentioned
maximum in work, our previous findings may be explained either on the
basis of a shift of these maxima to the left or on a change of shape of
the EW and EET relationships. Therefore, the second aim of the present
study was to evaluate relationships of EW and EET vs. regional
afterload before and after producing regional myocardial stunning.
Apart from the question of how regional EW-es and
EET-es relationships are affected by regional stunning,
it is presently unknown whether and how stunning of a region influences
the nonstunned region. Hence, we evaluated the relationship of
EW-es and EET-es for the nonstunned
region after stunning another region. All of the above-proposed studies
were conducted in open-chest pigs with a well-accepted protocol to
induce myocardial stunning.
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MATERIALS AND METHODS |
General.
All experiments were performed in accordance with the "Guiding
Principles for the Care and Use of Animals" as approved by the
Council of the American Physiological Society and under the regulations
of the Animal Care Committee of the Erasmus University Rotterdam.
Instrumentation.
After an overnight fast, crossbred Yorkshire-Landrace pigs (30-39
kg, n = 9) were sedated with 20 mg/kg im
ketamine (Apharmo, Arnhem, The Netherlands), anesthetized with
15-20 mg/kg iv pentobarbital sodium (Apharmo), intubated, and
connected to a ventilator for intermittent positive-pressure
ventilation with a mixture of oxygen and nitrogen (1:2 vol/vol).
Arterial oxygen content and blood gases were kept within the normal
range [7.35 < pH < 7.45; 35 < PCO2 (mmHg) < 45; 100 < PO2 (mmHg) < 150] by adjusting, when necessary, the respiratory rate and tidal volume. Three 7-French (Fr)
fluid-filled catheters were placed in the superior caval veins for the
continuous infusion of 10-15
mg · kg
1 · h1 pentobarbital
sodium, the continuous infusion of saline, the administration of 4 mg
of the muscle relaxant pancuronium bromide (Organon Teknika, Boxtel,
The Netherlands) prior to thoracotomy, and the administration of the
specific negative chronotropic agent zatebradine (1-2 mg/kg,
courtesy of Dr. J. W. Dämmgen; Dr. Karl Thomae,
Boehringer Ingelheim, Biberach a/d Riss, Germany). Central aortic blood
pressure was monitored via an 8-Fr catheter positioned in the thoracic
descending aorta, whereas left ventricular pressure and its first
derivative were obtained with a 7-Fr micromanometer-tipped catheter
(Braun Medical, Uden, The Netherlands), which was inserted via the left
carotid artery. A latex balloon made in our laboratory was mounted on a
7-Fr fluid-filled catheter and inserted via the right femoral vein and
positioned in the inferior caval vein just above the diaphragm.
Inflation of this balloon reduced the preload for the left ventricle. A
7-Fr latex Fogarty catheter (Baxter Healthcare, Irvine, CA) was
inserted via the right carotid artery and positioned in the ascending
aorta. Inflation of this balloon gradually increased afterload for the
left ventricle.
After a midline sternotomy and after ligation of the left
mammarian artery and vein, a part of the second left rib was
removed, and the heart was suspended in a pericardial cradle. An
electromagnetic flow probe (Skalar, Delft, The Netherlands) was placed
around the ascending aorta to measure aortic flow. A small segment of the proximal part of the left anterior descending coronary artery (LADCA) was dissected free for placement of an electromagnetic flow
probe (Skalar) and an atraumatic clamp to occlude the LADCA. To obtain
local coronary venous blood samples, a cannula was inserted into the
great cardiac vein, which drains specifically the LADCA perfusion area
(2). Pacing leads were attached to the right atrial
appendage and connected to a pacing stimulator (model S9; Grass,
Quincy, MA). Rectal temperature was monitored throughout the experiment
and was maintained between 37°C and 38°C using external heating
pads, warming of the saline infusion, and coverage of the animals with blankets.
Two ultrasonic crystals (Triton Technology, San Diego, CA) were
positioned in the midmyocardium of both the anterior and posterior left
ventricular wall to measure the diameter of the left ventricle. The
diameter crystal in the anterior wall was positioned close to the LADCA
segment length crystals. The diameter crystal in the posterior wall was
positioned such as to optimize signal quality. Two pairs of ultrasonic
crystals were implanted in the midmyocardium of the distribution area
of the LADCA, each pair 10 mm apart, approximately at one-third of the
distance from apex to base. One pair was positioned in the direction of
the left ventricular outflow tract (as determined visually), whereas
the other pair was placed perpendicular to this direction. The distance
of 10 mm and the perpendicularity of the two pairs were assured using a
homemade device consisting of two perpendicularly fixed pairs of
needles. Similarly, two pairs of crystals were implanted in the
midmyocardium of the distribution area of the left circumflex coronary
artery (LCXCA), approximately at half the distance from apex to base.
One pair was positioned in the direction of the left ventricular
outflow tract, and the other pair was placed in the perpendicular
direction. The position of the crystals in the mid-myocardium was
verified at the end of the experiment.
Experimental protocol.
After a 30- to 45-min stabilization period, steady-state recordings of
hemodynamics and segment lengths in the two myocardial regions were
made during 10 respiratory cycles, and global arterial and regional
myocardial venous blood samples were collected. After these baseline
recordings were made, heart rate was lowered below 70 beats/min by
infusion of zatebradine and set at 100 beats/min with the external
pacemaker to exclude effects of alterations in heart rate. The baseline
measurements were repeated and followed by inflation of the balloon
located in the inferior caval vein over a period of 15 s to create
a series of 20-25 beats with a gradual reduction of end-systolic
left ventricular pressure of ~50-60 mmHg. During the inflation
of the balloon, the respirator was switched off. The period of 15 s is sufficiently short to prevent reflex-mediated changes in
contractility (1). Moreover, before the heart was paced,
systolic, diastolic, and total heart cycle duration did not change in
our experiments up to 18 s (for definition of systole and
diastole, see below). After hemodynamic variables had resumed
preinflation values (differences in mean arterial pressure and in
maximum left ventricular pressure rise smaller than 4 mmHg and 100 mmHg/s, respectively), the balloon located in the ascending aorta was
then gradually inflated over a period of 10 s to create 10-20
beats with an increase of end-systolic left ventricular pressure of
~30-40 mmHg. The respirator was again switched off during this
procedure. The order of inflating the two balloons was randomized for
each measurement.
Subsequently, myocardial stunning was produced in the LADCA region by
two coronary (LADCA) occlusions of 10 min, separated by 10 min of
reperfusion. The last occlusion was followed by 30 min of reperfusion.
After this period, the steady-state measurements and the balloon
inflations as mentioned above were repeated.
At the end of each experiment, methylene blue was infused into the
LADCA, and the myocardium perfused by the LADCA was dissected and
weighed. In addition, the myocardium inside the segment crystals in
both LADCA and LCXCA regions was also dissected and weighed.
Data acquisition and analysis.
Left ventricular pressure, its first derivative, central aortic
pressure, aortic flow, coronary blood flow, left ventricular diameter,
and the regional segment length signals were digitized (sample rate:
125 Hz) with a 12-bit analog-to-digital converter connected to an
AT-based personal computer (AT-CODAS; Keithley Instruments, Gorinchem,
The Netherlands) and stored on disk for offline analysis. Mean arterial
pressure, systolic arterial pressure, diastolic arterial pressure,
maximum left ventricular pressure rise, left ventricular end-diastolic
pressure, cardiac output, stroke volume, and systemic vascular
resistance were calculated following standard procedures. Myocardial
oxygen consumption of the LADCA perfusion area
(M
O2, in
J · beat1 · m3) was
calculated as the product of coronary blood flow and the difference in
arterial and coronary venous oxygen content divided by the heart rate
and the mass of the LADCA perfusion area. The energy generated by 1 ml
of O2 was set equal to 20 J (22). Left ventricular wall stress (, in N/m2) and strain (
,
dimensionless) were calculated offline by applying the formulas
described in the APPENDIX. End-systolic stress-strain relationships were determined from the combined pre- and afterload changes by determining left ventricular end-systolic stress-strain points using an iterative fitting algorithm, as described before (26). Briefly, to determine these points, a linear
relationship was applied in which elastance was defined as
/( 
0), where 0 is the
strain at zero wall stress. To initiate the iteration, 0
was set to zero and elastance was calculated. End-systolic stress-strain points were determined for each heartbeat as the point at
which elastance was maximal. Subsequently, a new 0 value was calculated using a linear least-squares fit through the
end-systolic points. The new 0 value was used to start a
new cycle as described above. This procedure was repeated until
0 did not differ more than 1% from the 0
determined during the previous cycle. The stress and strain at these
points were defined as end-systolic stress (es) and
end-systolic strain (es).
As the end-systolic stress-strain relationship was often curvilinear,
the end-systolic points were also fitted to the following second-order
polynomial regression equation: = c3 · 2 + c2 · + c1 (14, 26), using the
least-squares technique. If the coefficient c3
was not significantly different from zero (P 
0.05),
the linear equation was selected. If c3 was
negative (concave to the strain axis), the second-order polynomial was selected. If c3 was positive (convex to the
strain-axis) and the fitted curve did not intersect the strain-axis,
the data were fitted to the third-order polynomial = c4 · 3 + c3 · 2 + c2 · + c1. The slope of the end-systolic stress-strain
relationship, called the end-systolic elastance
(Ees, in N/m2), was used as an index
of contractility. As this slope is strain dependent,
Ees was calculated as the local slope at a
stress, corresponding to a left ventricular pressure of 80 mmHg at
baseline. This value was identical during the experiment for each pig.
The area enclosed by the left ventricular stress-strain loop during a
single heartbeat was calculated as the EW of the myocardial region (in
J/m3), normalized per unit of volume (10, 19,
28). Stress-strain area (SSA, in J/m3), the regional
equivalent of the pressure-volume area (PVA), an index of total
ventricular work, was calculated as the area enclosed by the
end-systolic and end-diastolic relations and the systolic trajectory of
the stress-strain loop (14, 24). Potential energy (PE, in
J/m3) was calculated by subtracting EW from SSA. The
regional EET (in %) was calculated as (EW/SSA) · 100%. The
situation before pre- and afterload changes was called the working
point, and es, SSA, EW, PE, and EET at the working point
were called es,wp, SSAwp, EWwp,
PEwp, and EETwp.
Subsequently, for each animal, EW and EET were plotted versus
es, and the relationships were normalized such that
EWwp, EETwp, and es,wp were
equal to unity before stunning. To account for changes in the
coordinates of the working point for es, EW, and EET
after stunning, the relationships were normalized such that the
coordinates of the working point were equal to the ratio of the mean
value after stunning and the mean value before stunning. Each
relationship was linearly interpolated to obtain a range of equal
es coordinates for each animal. Maximal EW
(EWmax), maximal EET (EETmax), and their
respective es values (es,EWmax and
es,EETmax) were determined from the normalized curves.
The respective differences between EWwp,
EETwp, and es,wp and EWmax, EETmax, es,EWmax and
es,EETmax (
EW, EET, EW,
EET) were determined. Finally, the intervals
on the es axis (surrounding es,wp), in which EW and EET did not
decrease significantly from EWwp and EETwp,
were determined using paired t-tests. The left and right
borders of these intervals are referred to as left and right
significance borders. To determine the dependence of EW and EET on
es, the slopes of the EW-es and
EET-es relationships at these significance borders were
calculated. The normalized curves from different animals were averaged
at each normalized es coordinate showing at least five
EW or EET measuring values, and the average curve was filtered applying
a moving average filter.
Statistics.
For all hemodynamic, contractile, and energetic parameters, the effect
of infusion of zatebradine and subsequent pacing at 100 beats/min and
of LADCA stunning and, for the contractile and energetic parameters
(except MO2), the difference between the LADCA and LCXCA regions was tested by a two-way ANOVA for repeated measurements, followed by Student-Newman-Keuls post hoc tests for
multiple comparisons. As MO2 was only
measured in the LADCA perfusion area, a one-way ANOVA for repeated
measurements was performed. Because we could not describe the
EW-es and EET-es relationships with a
regression equation, we could not perform an ANOVA to test for changes
in these relationships. To overcome this problem, we applied a
three-way ANOVA for repeated measures, using es,
stunning, and myocardial region as within-subject factors. Because
within-subject factors have to be discrete, we divided the range of
es values in six equal ranges, using the
mid-es value of each range and the mean of the
accompanying EW or EET values. Next, paired t-tests were
employed for both perfusion areas to test whether EW and EET
differed from zero. Paired t-tests were also performed to
test the influence of LADCA stunning on the parameters of the
EW-es and EET-es relationships.
The influence of Ees on the curve parameters
EWmax, EW, EETmax, and EET was tested
using linear regression on the pooled data of the LADCA and LCXCA
perfusion areas before and after stunning. To validate pooling of the
data, the two perfusion areas were encoded using a slope- and an
intercept-dummy variable, and significance of these dummies was tested
using an F-test. For the regressions, one data point with an
Ees that was 3.7 standard deviations higher than
the mean Ees was removed. No regression
equations are given.
All data have been expressed as means and 95% prediction intervals.
P < 0.05 was considered significant. Unless stated
otherwise, only significant changes are mentioned in the
RESULTS.
| |
RESULTS |
Systemic hemodynamics.
Lowering heart rate by zatebradine from 109 ()
beats/min to below 70 beats/min and subsequent pacing to 100 beats/min
did not affect any hemodynamic parameter significantly, except for the
maximum left ventricular pressure rise, which decreased by 13% (Table
1). Stunning of the LADCA perfusion area
decreased diastolic arterial pressure (15%) and the maximum left
ventricular pressure rise (18%). Cardiac output and stroke volume both
decreased by 23%, and systemic vascular resistance increased by 17%.
Regional contractile and energetic parameters.
At baseline, all contractile and energetic parameters were the
same between the LADCA and LCXCA regions, except for SSAwp in the LCXCA region, which was 89% of SSAwp in the LADCA
region. Lowering heart rate from 109 to below 70 beats/min and pacing at 100 beats/min had no effect on Ees,
0, es,wp, EWwp,
PEwp, and EETwp in both the LADCA and the LCXCA
perfusion area, except for SSAwp of the LCXCA
perfusion area, which decreased by 15% (Table
2). There was no difference between
the LADCA and LCXCA region for any parameter, while
MO2 of the LADCA perfusion area was also
unaffected. In the LADCA perfusion area, stunning reduced Ees by 38%, whereas 0 increased
by 10%. EWwp decreased by 36%, causing a decrease in
EETwp of 27%. SSAwp and
PEwp remained unchanged, although PEwp tended
to increase. Stunning did not affect
MO2. Stunning the LADCA perfusion area
had no effect on any of the contractile and energetic parameters of the
LCXCA perfusion area, except for EWwp, which decreased by
23%. Stunning also induced differences between the LADCA and LCXCA
perfusion areas for Ees, 0, PE,
and EET.
EW-es relationships.
Before stunning, the individual EW-es relationships
displayed a maximum in EW at 14.1 (7.8-20.4) × 102 J/m3 at an es of 15.3 (10.1-20.6) × 103 N/m2 (LADCA,
before stunning; Fig. 1) and 11.9 (7.9-15.8) × 102 J/m3 at an
es of 15.9 (12.3-19.5) × 103
N/m2 (LCXCA, before stunning). There was no significant
difference between the two curves. The normalized average curves of
both the LADCA and LCXCA regions displayed a steep descending
relationship during es reduction; the slopes of these
curves at the left significance border were 3.46 (0.63-6.29)
(LADCA) and 2.62 (0.06-5.30) (LCXCA) (Fig.
2, A and C).
However, they displayed a flat relationship during es
increments; the slopes of the curves at the right nonsignificant maxima
were 0.68 (1.61-0.26) (LADCA) and 0.83 (1.84-0.19) (LCXCA). Consequently, a decrease in es had a
strong influence on EW; only a 2.8% (LADCA) or 1.3% (LCXCA) decrease
in es from the working point already resulted in a
significant decrease in EW. In contrast, an increase in
es did first result in an increase in EW, but a further
increase in es did not result in a significant decrease
in EW. Because of this increase in EW, both EW and EW were different from zero; EW being 0.35 (0.26-0.45) and 0.39 (0.15-0.64) and EW being 0.18 (0.10-0.27) and 0.21 (0.07-0.34) for the LADCA and LCXCA
regions, respectively.
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Fig. 1.
Example of an EW-es relationship of the
left anterior descending coronary artery (LADCA) perfusion area before
stunning of the LADCA perfusion area. See text for details. EW,
external work; es, regional end-systolic stress.
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Fig. 2.
Averaged curves of normalized EW-es relationships.
A: LADCA before stunning. B: LADCA after
stunning. C: left circumflex coronary artery (LCXCA) before
stunning. D: LCXCA after stunning. Solid curves are averaged
curves; broken lines are 95% prediction intervals. The horizontal line
denotes the part of the curve in which EW is not significantly
decreased from EW at the working point. If this line extends to the end
of the data, no significant decrease in EW was found. See text for
details.
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Stunning the LADCA region changed the shape of the EW-es
curve and shifted it downward (Fig. 2B). Therefore, the
curves became different between the LADCA and LCXCA regions. Now both a
decrease (10%) and an increase (13%) in es caused a
significant reduction in EW in the LADCA region, whereas in the LCXCA
region a 1.1% decrease in es still caused a significant
decrease in EW and an increase in es did not cause a
significant decrease in EW. The slopes at the left and right
significance border for the LADCA region did not change significantly,
however, and remained at 1.86 (1.07-2.65) (left)
and 1.06 (2.03 to 0.09) (right). Furthermore, EW decreased to 0.08 (0.11-0.27,
P > 0.05 vs. zero), and EW decreased to 0.07 (0.01-0.13, P < 0.05 vs. zero). In addition, the
es coordinate of the maximum showed a tendency to
decrease by 11% [to 13.7 (8.37-19.0) × 103
N/m2, P = 0.09], and the EW coordinate of
the maximum of the EW-es curve decreased by 39% to 8.65 (3.16-14.1) × 102 J/m3. For the
LCXCA region, the ANOVA showed a significant change in the curve due to
LADCA stunning (Fig. 2D). However, only
EWmax decreased by 22% to 9.11 (5.11-13.1) × 102 J/m3 at an
unchanged es of 13.1 (11.1-15.1) × 103 N/m2. The slopes of the curve at the left
significance border and the right nonsignificant maximum also remained
unchanged at 1.68 (0.27-3.08) and 0.76 (1.49 to
0.01), respectively.
EET-es relationships.
The individual EET-es relationships displayed a maximum
in EET of 78 (74-83)% at an es of
10.8 (7.56-14.0) × 103 N/m2 (LADCA,
before stunning, Fig. 3) and at 74 (69-79)% also at an es of 10.8 (6.89-14.6) × 103 N/m2 (LCXCA,
before stunning) after changing es over a large range of
values. There was no significant difference between the two curves. The
normalized average curves of both the LADCA and LCXCA regions displayed
a flat profile over a relatively large range of es
values (Fig. 4, A and
C). Outside this region EET decreased more sharply.
Therefore, a 25% (LADCA) or 38% (LCXCA) reduction in
es was necessary to induce a significant decrease in
EET. Also, a 3% (LADCA) or 34% (LCXCA) increase in es
resulted in a significant decline in EET. The slopes of the curves at
the left significance border were 0.54 (0.07-1.02) (LADCA) and
1.01 (0.15-2.17) (LCXCA). The slopes at the right significance
border were 0.10 (1.09-0.89) and 0.79 (1.32 to 0.26),
respectively. The EET was not significantly different
from zero, at 0.04 (0.11-0.04) (LADCA) and 0.04
(0.17-0.10) (LCXCA). Although the EET coordinates of the working
point were different from the maximum (P < 0.05),
EET was only 0.04 (0.02-0.06) (LADCA) and 0.08 (0.04-0.13)
(LCXCA).
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Fig. 3.
Example of an EET-es relationship of the
LADCA perfusion area before stunning of the LADCA perfusion area. See
text for details. EET, efficiency of energy transfer.
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Fig. 4.
Averaged curves of normalized EET-es relationships.
A: LADCA before stunning. B: LADCA after
stunning. C: LCXCA before stunning. D: LCXCA
after stunning. Solid curves are averaged curves; broken lines are 95%
prediction intervals. The horizontal line denotes the part of the curve
in which EET is not significantly decreased from EET at the working
point. If this line extends to the end of the data, no significant
decrease in EET was found. See text for details.
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Stunning the LADCA region changed the shape of the
EET-es curve and shifted it downward (Fig.
4B). The curve now displayed a maximum at 58.9 (45.7-72.2)% (a decrease of 24%, P < 0.05 vs. before stunning), at an es of 10.8 (6.46-15.2) × 103 N/m2 (P > 0.05 vs.
before stunning). Still, a 29% decrease in es and a 1%
increase in es caused EET to decrease significantly. The
shape of the EET-es curve changed in such a way that EET became more sensitive to both increments and decrements in
es as the slope of the EET-es
relationship at the left significance border increased 5-fold to 3.33 (1.33-5.34) and the negative slope at the right significance
border increased 19-fold to 1.87 (3.87-0.12). The
EET and EET remained unaffected at 0.05
(0.11-0.01) and 0.07 (0.03-0.12), however. In the LCXCA
region, stunning had no significant effect on the EET-es
curve (Fig. 4D). The curve displayed a maximum in EET at
76.6% (66.9-86.4) with an es coordinate of 7.86 (5.04-10.7) × 103 N/m2. A decrease
in es did not cause a significant decrease in EET, but a
0.6% increase in es caused a significant decrease in
EET. The slope at the left nonsignificant minimum was 1.26 (3.78-6.30), and the slope at the right significance border was
0.07 (3.07-3.22).
Relationship with contractility.
In the regression between Ees and
the parameters EWmax, EETmax, EW,
and EET, only EWmax and EETmax showed a
significant positive relationship with Ees (Fig.
5). Further analysis revealed that both
the relationships between EWmax and
Ees and between EETmax and
Ees were different for the LADCA and LCXCA
perfusion areas.
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Fig. 5.
Relationships between end-systolic elastance
(Ees) and EWmax (A),
EW (B), EETmax (C), and EET
(D). Data from before and after stunning and from the LADCA
and LCXCA perfusion areas are pooled. For A and
C only,  = LADCA,  = LCXCA; for
B and D, all data are presented by the same
symbol (). EWmax, maximal regional EW;
EW, difference between maximal regional EW and regional EW at the
working point; EETmax, maximal regional efficiency of
energy transfer; and EET, difference between maximal regional
efficiency of energy transfer and regional efficiency of energy
transfer at the working point. See text for details.
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DISCUSSION |
Normal myocardium.
Our first aim was to evaluate whether regional EET and regional EW
displayed a maximum in relation to regional afterload, defined as
regional es. In a strict sense, only EET displayed a
maximum in the LADCA and LCXCA perfusion areas, as the relationship between regional EW and afterload showed an increase in EW without a
subsequent decrease after increments in afterload. These findings are
therefore partly in accordance with earlier studies (5, 7), in which both global EW and EET displayed a maximum and decreased with increasing afterload. A possible explanation for this
discrepancy is that in the present in vivo experiments, increments in
afterload are accompanied by increments in preload. We investigated the
effect of this possible pitfall by dividing EW at the working point and EW at the highest es by their respective
end-diastolic strains, a measure of regional preload. However, due
to the small increments in strain (1.4%), we still could not find a
significant decrease in EW at the highest es. Therefore,
we have to conclude that in the present settings the relationship
between EW and afterload increased to a plateau when afterload was increased.
The increase in EW with increasing afterload was 18-20% of the EW
at the working point, also when EW was corrected for preload changes.
In contrast, maximal EET was only 4-8% different from the EET at
the working point, whereas the two es values were not
different. Therefore, we conclude that in our experiments normal
myocardium operated at maximal EET rather than at maximal EW.
There is no consensus on whether global left ventricular power is
maximal under physiological conditions. For instance, in a modeling
study based on data of intact, conscious dogs, Burkhoff and Sagawa
(5) predicted that power is likely to be submaximal. However, if they used data from anesthetized, open-chest dogs, then a
maximization of power was predicted. In the present study measurements
were performed in anesthetized, open-chest swine, and we therefore
expected a maximization of power. However, in anesthetized patients
undergoing abdominal surgery, Kadoi et al. (13) found a
ventriculo-arterial coupling ratio in agreement with submaximal power.
In the same study, patients undergoing coronary artery bypass
surgery with a low ejection fraction had a ventriculo-arterial
coupling ratio suggesting maximization of power. Consequently, these
results indicate that, apart from myocardial dysfunction, species
differences may play an important role. To our knowledge, in swine,
ventriculo-arterial coupling has only been studied in the normal right
ventricle, also suggesting submaximal power (3).
Stunned myocardium.
Regional stunning of the LADCA perfusion area decreased contractility
in accordance with former studies (14). In addition, end-systolic 0 increased by 10%. In a former study, we
have shown that stunning causes increases in left ventricular volume at
zero pressure, independent of inotropic interventions
(15). The increase in 0 may therefore be
attributed to a decrease in elastic restoring forces, probably induced
by alterations in the extracellular collagen matrix and/or the cytoskeleton.
After stunning the LADCA perfusion area, both EW and EET displayed
maxima in relation to es. In accordance with decrements in EW and EET at the working point, the maxima in EW and EET were decreased compared with normal myocardium. The maximum of the EW-es relationship also tended to shift to the left, but
this change was not significant (P = 0.09).
EWmax was now only 7% higher than EW at the working point,
and es,EWmax was no longer different from
es,wp at the working point. As a consequence, the
working point was now similar to EWmax. To the best of our
knowledge, only relative changes in ventriculo-arterial coupling ratio
have been reported after regional stunning (30). From
these data it cannot be concluded whether power was maximized before or
after stunning.
A second effect of stunning was that both EW and EET became more
sensitive to increments in afterload. This is in agreement with our
former study in which we showed that both EW and EET, deduced from
pressure-segment length relationships, decreased more with increasing
afterload after myocardial stunning (9). As EET also
became more sensitive to decrements in es, afterload regulation became more critical in stunned myocardium. Changes in
preload did not influence this difference, because preload maximally
increased by 4% before stunning and 4.5% after stunning (P = 0.41). In the LCXCA perfusion area, however, the
relationship between EW at the working point and EWmax
remained unchanged. So, if we augment global afterload, then EW will
increase in the LCXCA perfusion area and decrease in the LADCA
perfusion area. Consequently, global afterload will not simultaneously
maximize EW in both myocardial regions. Because EET at the working
point does not change in relation to EETmax, both
regions still operate at EETmax. However, small changes in
afterload will immediately decrease EET in the stunned LADCA perfusion
area. From these findings, we conclude that EW and EET are regulated
separately in the two myocardial regions, and the LCXCA region does, at
least in porcine myocardium, not adapt itself to compensate for the
LADCA region.
In accordance with the oxygen consumption paradox of stunned myocardium
(8), steady-state myocardial oxygen consumption was
unchanged after myocardial stunning. In a former study we showed that
two periods of 10 min of ischemia caused ATP, ADP, and total adenine
nucleotides to decrease by 34%, 37%, and 33%, respectively, while
energy charge [defined as (ATP + 0.5 · ADP) · (ATP + ADP + AMP)1] remained unchanged (17). This
suggests an adequate ATP turnover despite a decrease in the
concentrations of each high-energy phosphate.
Relationship with contractility.
We studied the relationship between Ees and
EWmax, EETmax, EW, and EET in the LADCA
perfusion area. Although EW was decreased in stunned myocardium, we
could not show a positive relationship between EW and
Ees. A possible explanation might be that the range in EW was too small, because we did find a positive
relationship between Ees and EWmax.
This latter result was to be expected, because, apart from EW,
EWwp also decreased with myocardial stunning, in
accordance with former results (16). In that particular
study, we also showed a positive nonlinear relationship between
EETwp and Ees.
Underlying mechanism.
It is well accepted that myocardial stunning is the result of
disturbances in excitation-contraction coupling. As a consequence, Ees is decreased in stunned myocardium. Because
of the positive relationship between Ees and
EWmax, the decrease in Ees caused a
reduction in EWmax. EWwp, however, is not only
dependent on contractility but also on the regional afterload,
characterized by es,wp. Because regional afterload did
not decrease, due to a compensatory increase in systemic vascular
resistance (Table 1), EWwp decreased less than
EWmax, causing the reduction in EW.
Limitations.
The present study is based on the time-varying elastance concept, i.e.,
a single elastance changing over time as a model for the myocardium.
Hence, visco-elastic properties, kinetic energy, and the history effect
(4, 6, 18) are not accounted for. Although the effect of
these properties is considered small under physiological circumstances,
their contribution in stunned myocardium is presently unknown. In this
respect, the results of this study should be interpreted with caution.
In our in vivo model, we were not able to change preload and afterload
independently. Decreasing global left ventricular preload decreases not
only regional preload but also regional afterload, because both
regional wall thickness and curvature increase. On the other hand,
increasing global left ventricular afterload by inflating an
intra-aortic balloon decreases cardiac output and therefore increases
preload for the next beat. However, changes in preload were small, and
correcting for these increments in preload did not change our results significantly.
We used the posterior-anterior diameter to calculate regional stress in
both the LADCA and LCXCA perfusion areas, which is not completely
correct for the LCXCA perfusion area, especially after stunning. This
diameter may increase after stunning, due to stretch of the LADCA
perfusion area. Consequently, applying the curvature changes to the
LCXCA perfusion area may not be fully correct. However, because
es was unchanged after myocardial stunning in both
perfusion areas and Ees did not change in the
LCXCA perfusion area, the error introduced was probably negligible.
We assumed that the myocardial volume between the LADCA crystals
remained constant before and after induction of stunning. However,
Jennings et al. (12) showed that stunning causes about 8%
increase in myocardial cell volume due to increased water content. If
we assume that in our preparation myocardial volume between the
crystals increased by 8% as well, real wall thickness may have
increased by 2%. If so, we underestimated stress,
Ees, and EW before stunning by 2%. However,
es,wp showed a nonsignificant increase due to myocardial
stunning, which may be overestimated due to this limitation. Also, the
significant decrease in Ees and EW due to
myocardial stunning may be underestimated. Therefore, this limitation
does not seem to affect the reported alterations caused by
myocardial stunning.
As we measured regional MO2 by sampling
the great cardiac vein, this measurement only reflected tissue
MO2 during steady-state conditions, not
allowing us to study the relationship between myocardial efficiency
(EWwp/MO2) and regional
afterload on a beat-to-beat basis. Therefore, it remains unresolved
whether in our study the myocardium operated at maximal myocardial efficiency.
This study was performed in pentobarbital-anesthetized swine. Because
pentobarbital is known to decrease baseline myocardial contractility
and to attenuate cardiovascular reflexes, caution is therefore
warranted when the present results are extrapolated to the awake animal.
Conclusions.
In this study, regional myocardium before stunning operated at maximal
EET rather than at maximal EW, partially in accordance with findings in
the global left ventricle. As a consequence, recruitment of EW was
possible by increasing regional afterload. After myocardial stunning,
the myocardium operated both at maximal EW and at maximal EET. In
addition, both EW and EET became more sensitive to afterload. The
reduced contractility of stunned myocardium is thought to have an
important effect on these relationships.
| |
APPENDIX |
To calculate regional stress and regional strain, we used the
following approach. We assumed a concentric spherical geometry of both
the regional endocardium and epicardium. Wall tension (T) for a sphere, according to Laplace, is
|
(1)
|
in which P is the cavity pressure and r is the radius
of the left ventricle. For a rectangular block of tissue in the
ventricular wall between two perpendicularly oriented pairs of
crystals, a longitudinal segment length (SLL,
which is in a plane through the long axis of the left ventricle), a
transversal segment length (SLT, perpendicular
to SLL), a force oriented parallel to
SLL (FL), and a force oriented
parallel to SLT (FT) are defined
(Fig. 6). The equations for the two
forces are then
|
(2)
|
and
|
(3)
|
Dividing these forces by the respective areas
AL and AT delivers the
wall stresses in both directions. As the number of fibers producing the
forces FL and FT being present in the areas
AL or AT will not change
over the cardiac cycle, normalization to fiber stress would not be
affected by the changes in the respective areas. We therefore defined a
reference state (indicated by the subscript ref) on which all
subsequent stress calculations were based. In formula
|
(4)
|
and
|
(5)
|
in which Wth,ref is the reference wall
thickness. As the volume of the block of tissue (Vref)
remains constant during the cardiac cycle,
Wth,ref can also be written as
|
(6)
|
Dividing Eq. 2 by Eq. 4, and Eq. 3 by Eq. 5, and combining with Eq. 6 gives
us
|
(7)
|
and
|
(8)
|
in which L and T are the
longitudinal and transversal wall stress, respectively. Mean average
wall stress was defined as the geometric mean (29)
according to
|
(9)
|
Similarly, mean regional strain () was derived from the
geometric mean according to
|
(10)
|
View larger version (15K):
[in this window]
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|
Fig. 6.
Schematic representation of the forces working on a block
of myocardial tissue. SLT, transversal segment
length; SLL, longitudinal segment length;
Wth, wall thickness; AT,
transversal segment area; AL, longitudinal
segment area; FT, transversal force; and FL,
longitudinal force. For calculations, see APPENDIX.
|
|
| |
ACKNOWLEDGEMENTS |
The technical assistance of Jan R. van Meegen and Rob H. van Bremen
is gratefully acknowledged.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: R. Krams, Thoraxcenter, Erasmus Univ. Rotterdam, PO Box 1738, 3000 DR
Rotterdam, The Netherlands (E-mail: krams{at}tch.fgg.eur.nl).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 17 September 1999; accepted in final form 30 March 2000.
| |
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ABSTRACT
INTRODUCTION
