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490
Dynamic Relation Between Myocardial
Contractility and Energy Metabolism
During and Following Brief Coronary
Occlusion in the Pig
Gregory G. Schwartz, Saul Schaefer, Dieter J. Meyerhoff, Joel Gober, Patricia Fochler,
Barry Massie, and Michael W. Weiner
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Changes in high-energy phosphate metabolism may be important in the regulation of
myocardial contractile function during ischemia. This study sought to determine the dynamic
relation between myocardial contractile function and high-energy phosphate metabolism
during and following brief (24-second) coronary occlusion, when large and rapid changes in
both parameters occur. Eight anesthetized, open-chest pigs were instrumented with a Doppler
flow probe and occluder on the anterior descending coronary artery, segment length crystals in
the anterior left ventricular wall, and a surface coil for phosphorus-31 nuclear magnetic
resonance spectroscopy. Phosphorus-31 spectra were reconstructed with a 4.8-second time
resolution by summing corresponding short blocks of data from multiple occlusions. Metabolic
and functional parameters were unchanged during the first 4.8 seconds of occlusion. During the
remainder of occlusion, phosphocreatine progressively declined to 66±3% of control, inorganic
phosphate rose to 170+±8% of control, and segment shortening fell to 25±9%o of control. A
strong linear correlation was found between dynamic changes in segment shortening and
phosphocreatine (r2=0.97), inorganic phosphate (r2=0.96), and the ratio of phosphocreatine to
inorganic phosphate (r2=0.98) during occlusion. At any level of the ratio between phosphocreatine and inorganic phosphate, segment shortening was greater during reflow than during
occlusion. The close, dynamic relation between segment shortening and phosphorus metabolites supports the regulation of contractility by changes in energy metabolism or its by-products
during ischemia. During reactive hyperemia, the high coronary flow rate may be an independent factor modulating contractility. (Circulation Research 1990;67:490-500)
yocardial ischemia perturbs high-energy
phosphate metabolism in the cardiac myocyte and leads to a decline in contractile
function."2 For over 20 years, these observations
have led to hypotheses that cardiac contractility is
regulated by levels of myocardial high-energy phosphates or impaired by metabolic by-products of ischemia, such as H' or inorganic phosphate (Pi).3
M
From the Magnetic Resonance Unit and Cardiology Section,
Veterans Administration Medical Center, and the Cardiovascular
Research Institute and Departments of Medicine and Radiology,
University of California, San Francisco, Calif.
Supported in part by National Institutes of Health awards
1K11-HL-02155 (G.G.S.), K08-HL-02131 (S.S.), and R01AM-33923 (M.W.); the American Heart Association, California
Affiliate (S.S.); Philips Medical Systems; and the Veterans Administration Medical Research Service (M.W.W., B.M.).
Address for correspondence: Gregory G. Schwartz, MD, PhD,
Cardiology Section (lllC), VA Medical Center, 4150 Clement St.,
San Francisco, CA 94121.
Received October 20, 1989; accepted April 3, 1990.
Because of the limited temporal resolution of metabolic measurements made by direct biochemical
techniques or by nuclear magnetic resonance (NMR)
spectroscopy, most of the data supporting these
hypotheses in intact animals has stemmed from studies of prolonged myocardial ischemia or hypoxia.4-7
However, the most rapid and pronounced changes
in myocardial contractile function and energy metabolism occur during the first 30 seconds of ischemia
and during the initial period of recovery after a brief
ischemic interval.8-13 Elucidating the dynamic relation between such large and rapid changes in cardiac
contractile function and energy metabolism may help
define the mechanisms by which cardiac contractility
is regulated during and following ischemia.
In addition to changes in energy metabolism, other
factors may have contributory, if not primary, roles in
the regulation of contractile function in the intact
animal. For example, an increase in coronary flow or
perfusion pressure may independently augment myo-
Schwartz et al Dynamic Changes of Myocardial Function and Energy Metabolism
cardial contractility. This observation has been
termed the Gregg phenomenon.1415 With release of a
brief coronary occlusion, coronary blood flow rises to
several times its control level during reactive hyperemia; however, it is unknown whether myocardial
contractile function is affected by this elevation of
coronary blood flow.
The purpose of this study was to determine the
dynamic relation between changes in myocardial
contractile function and high-energy phosphate
metabolism during brief coronary occlusion and subsequent reflow in the in situ, blood-perfused heart.
To augment the temporal resolution of the metabolic
measurements, 31P NMR spectra were reconstructed
from corresponding brief time intervals of repeated,
identical interventions.
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Materials and Methods
Animal Preparation
Eight female Yorkshire-Landrace pigs weighing
30-40 kg were used. After premedication with ketamine HCl (20 mg/kg i.m.), anesthesia was induced
in six pigs with halothane (3%) by face mask and
sodium pentobarbital (10 mg/kg i.v.). In two pigs,
anesthesia was induced with a-chloralose (150 mg/kg
i.v.). Normal saline (500 ml i.v.) was administered
rapidly with induction of anesthesia, followed by a
continuous infusion of 75 ml/hr. After endotracheal
intubation, the animals were mechanically ventilated
with oxygen by a pressure-cycled respirator. Ventilatory rate and tidal volume were adjusted to maintain
arterial pH between 7.30 and 7.45 with Po2 greater
than 100 mm Hg. Anesthesia was maintained with
halothane (0.5-1.0%) and sodium pentobarbital (1-2
mg/kg i.v. every 30 minutes) in six pigs and with
a-chloralose (20 mg/kg i.v. every 30 minutes) in two
pigs.
An 8F fluid-filled introducer sheath was inserted in
a carotid artery for monitoring of arterial pressure. A
7F pigtail catheter was advanced through the sheath
into the left ventricle for pressure measurement. The
heart was exposed via a median sternotomy, and two
proximal segments of the left anterior descending
coronary artery were dissected free for placement of a
hydraulic cuff occluder (In Vivo Metric, Healdsburg,
Calif.) and a perivascular Doppler flow probe (Crystal
Biotech Inc., Holliston, Mass.). The occluder was
placed as proximally as possible on the left anterior
descending coronary artery to obtain a large ischemic
region. In no case did a major diagonal branch originate proximal to the occluder. Bipolar pacing wires
were inserted in the left atrial appendage.
The ischemic region was defined by inflating the
occluder until an area of gross cyanosis and akinesis
was clearly demarcated on the anterior left ventricular surface. A two-turn, 2.5-cm diameter surface
coil tuned to the 31P resonance frequency was glued
with cyanoacrylate in the central portion of this
region. A pair of ultrasonic dimension gauges (Triton
Technology, San Diego) was implanted 1 cm apart
491
along the axis of fiber orientation16 in the subendocardium 1-2 mm adjacent to the surface coil. In all
pigs, the visibly ischemic region was much larger than
the area encompassed by the coil and dimension
gauges.
Segment shortening and coronary flow velocity
were measured with a Triton sonomicrometer and
flowmeter, respectively. Aortic and left ventricular
pressures, left ventricular dP/dt, coronary flow velocity, subendocardial segment length, and the intramyocardial electrogram (from the dimension gauges)
were recorded on a multichannel recorder (Gould,
Cupertino, Calif.).
Experimental Protocol
The pig was placed in a 1-m bore Philips Gyroscan
NMR spectrometer (Shelton, Conn.), operating at
2.0 T. Heart rate was maintained at 100 beats/min by
atrial pacing. The pacing stimulus was used to gate
the spectrometer acquisitions. To avoid radiofrequency noise introduced by wires leading into the
spectrometer bore, the stimulus was transmitted to
the spectrometer console by a telemetry system
(Hewlett-Packard, Palo Alto, Calif.).
After the phosphorus surface coil had been tuned
to proton frequency (85.9 MHz) with a GordonTimms arrangement,17 the magnet was shimmed on
cardiac water protons to an average linewidth of 25
Hz. The surface coil was then tuned to phosphorus
frequency (34.8 MHz). A small glass vial containing
hexamethylphosphorous triamide, placed in the center of the coil, served as a standard for determining
the phosphorus 900 pulse length at the center of the
coil. Spectroscopy was then performed with 1800
pulses gated 50 msec after the atrial pacing stimulus
(at end diastole) of every second cardiac cycle,
resulting in a repetition time of 1.2 seconds. A 1800
pulse length at the center of the coil was selected for
data acquisition on the basis of computer simulations18 to provide maximal weighting of the NMR
signal at a depth of approximately 0.7 cm from the
coil, in the region where segment shortening was
measured. However, this pulse length also allowed
some spectral contribution from 2,3-diphosphoglycerate (DPG) in left ventricular cavity blood.
The experimental intervention was a 24-second
occlusion of the left anterior descending coronary
artery, followed by complete release of the occlusion.
With each intervention, spectroscopy was performed
over a 2-minute interval spanning a 34-second preocclusion control period, the 24-second occlusion,
and 62-second recovery following occlusion release.
Groups of four successive acquisitions, each group
spanning 4.8 seconds, were stored separately.
Left anterior descending coronary artery occlusion
(24 seconds) was repeated a total of 20 times at
5-minute intervals. Measurement of coronary flow
and segment shortening simultaneous with NMR
acquisitions introduced excessive radiofrequency
noise in the NMR receiver. Therefore, these data
were obtained during different occlusions. Coronary
492
Circulation Research Vol 67, No 2, August 1990
flow and segment shortening were measured during
occlusions 1-3, 9-12, and 18-20. Spectroscopy was
performed during occlusions 4-8 and 13-17. Before
spectrosocpy, the cables from the flow probe and
dimension gauges were disconnected from the flowmeter and sonomicrometer and coiled inside the
magnet bore; the tuning and matching of the surface
coil were then readjusted, if necessary.
Control (nonischemic) hemodynamic measurements and a control spectrum of 40 acquisitions were
obtained before the first coronary occlusion and following every 3-5 occlusions thereafter. At the conclusion of an experiment, the pig was killed with a lethal
overdose of sodium pentobarbital. The position of the
segment length crystals in the subendocardium was
confirmed in all pigs by postmortem inspection.
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Data Analysis
Systolic segment shortening was computed according to the method of Theroux et al.8 End-diastolic
segment length was measured at the peak of the
intramyocardial ventricular electrogram, and endsystolic segment length was measured 20 msec before
peak negative left ventricular dP/dt. The timing intervals were established with a short length of fluidfilled tubing before the pig was placed in the spectrometer. Percent segment shortening was calculated
as 100 x (end-diastolic- end-systolic length)/enddiastolic length. Coronary blood flow velocity and
segment shortening were averaged during the same
4.8-second intervals as the NMR measurements.
At 2-T field strength, sufficient NMR data cannot
be acquired in 4.8 seconds to yield a useful 31P
spectrum. To improve temporal resolution, 4.8second blocks of data, each consisting of four acquisitions, were summed from the corresponding time
intervals of 10 interventions. Thus, 40 acquisitions
were used to reconstruct a phosphorus spectrum
from each 4.8-second interval preceding, during, and
following coronary occlusion.
The summed free induction decays were processed
by exponential multiplication with line broadening of
20 Hz, convolution difference with a line broadening
of 200 Hz and a convolution factor of 0.9, fast Fourier
transformation, and phasing with zero- and firstorder corrections. Peak position and height were
determined for Pi including superimposed 2,3-DPG,
phosphocreatine (PCr), and the 3-phosphate of
ATP. To allow adequate time for the phosphorus
metabolites to reach a steady state of partial saturation, the first eight acquisitions during the control
period of each intervention were not analyzed. During the remaining 24 seconds of the preocclusion
control period, the average peak height of each
metabolite was computed for each pig. During each
ensuing occlusion and postocclusion time interval,
the peak height of each metabolite was normalized to
its average preocclusion control value. We have
demonstrated (unpublished data) that the linewidths
of PCr and 3-ATP do not change appreciably during
or following brief coronary occlusion; therefore, nor-
TABLE 1. Effect of Repeated Brief Coronary Occlusion on Metabolic and Functional Parameters
SS (%)
PCr/Pi
PCr/,3-ATP
End
End
Beginning End
Beginning
Beginning
19±3
2.0±0.2 19±3
1.9±0.1
2.5±0.3
2.3±0.2
p=0.49
p=0.25
p=0.19
Beginning and end refer to the total period of data collection.
Metabolite values are expressed as ratios of peak heights. All
values are mean±SEM. PCr, phosphocreatine; Pi, inorganic phosphate; SS, segment shortening.
p values computed with paired t tests (n=8).
malized changes in metabolite peak height should
closely approximate normalized changes in peak
area.
During and immediately following ischemia, intracellular myocardial pH was estimated from the chemical shift of the Pi peak'9; however, spectral overlap of
Pi and 2,3 -DPG precluded accurate pH determination under nonischemic conditions.
Segment shortening and metabolite peak heights
for each pig were normalized to the control levels for
that animal. The normalized data from all eight pigs
were then pooled. In the pooled data, the significance of changes from control in each occlusion and
postocclusion time interval were assessed by Student's t test with a Bonferroni correction20 for 18
comparisons (five occlusion and 13 recovery intervals). A value of p<0.05 was considered statistically
significant. Data are reported as mean±SEM.
Results
Under control conditions, systolic, diastolic, and
mean aortic pressures were 74±3, 54±4, and 64±3
mm Hg, and systolic segment shortening was 19±3%.
The PCr/,f-ATP peak height ratio was 2.0±0.2, with
half-height linewidths of PCr and ,B-ATP of 1.2±0.1
and 1.4±0.1 ppm, respectively. The signal-to-noise
ratios for PCr and ,B-ATP were 8.3 ±0.4 and 4.8 ±0.3.
With occlusions spaced 5 minutes apart, there
were no changes in systemic hemodynamics, coronary
blood flow, or segment shortening, either under
control conditions or in response to occlusion, during
the course of the experiment. There were also no
cumulative changes in control phosphorus spectra.
Table 1 compares metabolic and functional data
obtained under control (nonischemic) conditions at
the beginning and the end of data acquisition. The
absence of discernible persistent effects of repeated
brief coronary occlusion validates the technique of
spectral reconstruction using acquisitions from successive interventions.
Figure 1 shows typical recordings of segment
length and arterial pressure with corresponding
phosphorus NMR spectra reconstructed from control, ischemic, and recovery time intervals. Normalized phosphorus metabolite peak heights during each
4.8-second interval are listed in Table 2, along with
calculated intracellular pH values. Table 3 lists normalized end-diastolic and end-systolic segment
Schwartz et al Dynamic Changes of Myocardial Function and Energy Metabolism
CL
C
B
A
493
E
E
Q! 7S
so4
<0
1 "c
-
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PCr
10.0
-10.0
0.0
[p
p
m]
-20.0
0.0
10.0
[ p p m]
-10.0
-20.0
10.0
o.0
-10.0
-20.0
[ p p m]
FIGURE 1. Top panel: Segment length in the subendocardium of the anterior left ventricle and aortic blood pressure recorded
before, during, and following 24-second coronary occlusion. Heart rate is 100 beats/min. Bottom panel: Representative 31P nuclear
magnetic resonance spectra reconstructed from corresponding 4.8-second time intervals. Panel A: Preocclusion control interval.
Panel B: Occlusion (19.2-24 seconds). Panel C: Reflow (19.2-24 seconds). Pi inorganic phosphate; 2,3-DPG, 2,3diphosphoglycerate; PCr, phosphocreatine.
length, segment shortening, and coronary blood flow
velocity during each of these intervals. Metabolite
peak height and segment shortening data are plotted
in Figure 2.
During the first 4.8 seconds of occlusion, there were
no detectable changes in any phosphorus metabolite
peaks, nor in segment shortening (Tables 2 and 3).
Beginning in the second time interval of occlusion
(4.8-9.6 seconds) and continuing through the remainder of occlusion, PCr peak intensity declined and Pi
rose, with little change in ,3-ATP. Concomitantly,
end-diastolic segment length increased slightly and
end-systolic segment length increased markedly,
resulting in a progressive decline of systolic segment
shortening. By the last time interval of occlusion
(19-24 seconds), PCr (normalized to its control value)
fell to 0.66±0.03, and normalized Pi rose to 1.70±0.08.
A slight decrease in the 13-ATP peak was noted at the
end of occlusion and in the early recovery period, but
this trend did not achieve statistical significance. Segment length (normalized to control) rose to 1.06+0.08
at end-diastole and 1.25 ±0.11 at end-systole, resulting
in a decline of segment shortening to 5±+2%
(0.25+±0.11 normalized to control). Segment shortening, PCr, and Pi were all still changing when the
occlusion was released at 24 seconds (Figure 2);
therefore, it is reasonable to expect that longer occlusions would have caused even more severe metabolic
and functional derangements (e.g., net systolic segment expansion).
With coronary occlusion, both systolic and diastolic
aortic pressure fell by 3-7 mm Hg, with occlusion
release blood pressure returned to control within
10-15 seconds. Left ventricular end-diastolic pressure increased by 1-2 mm Hg during occlusion from
its control value of 5 + 1 mm Hg. Reactive hyperemia
accompanied occlusion release, with coronary blood
flow velocity rising to 2.95 ±0.22 times control at the
peak of the response, 10-15 seconds after release.
Segment shortening began to recover in the first
postocclusion time interval (0-4.8 seconds after
release), while phosphorus metabolites began to
recover in the second postocclusion time interval
(4.8-9.6 seconds after release). By the interval 19-24
seconds after occlusion release, all phosphorus
metabolites and segment shortening had returned to
within +5% of their respective control values (Figure
2, Tables 2 and 3).
Beginning approximately 30 seconds after occlusion release, an undershoot in Pi peak height to
494
Circulation Research Vol 67, No 2, August 1990
TABLE 2. Metabolic Changes During and Following 24 Seconds of Coronary Occlusion
-3-ATP
PCr/Pi
PCr
Time (sec)
Pi
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Occlusion
0-4.8
4.8-9.6
9.6-14.4
14.4-19.2
19.2-24
Recovery
0-4.8
4.8-9.6
9.6-14.4
14.4-19.2
19.2-24
24-28.8
28.8-33.6
33.6-38.4
38.4-43.2
43.2-48
48-52.8
52.8-57.6
57.6-62.4
1.00+0.03
0.88±0.02
0.80±0.05
0.75 ±0.03*
0.66±0.03*
0.99±0.09
1.07±0.05
1.31±0.09
1.04±0.10
0.81±0.04
0.62±0.07*
1.05±0.03
0.95±0.05
0.95±0.06
1.53±0.14
1.70±0.08*
0.51±0.06*
0.38±0.03*
0.89±0.05
0.95+0.07
0.38±0.05*
0.47±0.05*
0.68±0.04*
0.90±0.06
1.07±0.13
1.06±0.08
1.19±0.14
1.38±0.16
1.12±0.08
1.26±0.07
1.29±0.12
1.30±0.13
1.15±0.08
Metabolite levels are normalized to their respective control values. pH values are
Pi, inorganic phosphate.
0.66±0.04*
0.71±0.04*
0.90±0.04
0.97+0.03
1.03±0.07
1.08±0.04
1.06±0.04
1.04±0.04
0.96±0.06
0.96±0.03
1.07±0.05
1.06±0.03
1.05±0.03
1.77±0.15*
1.52±0.10*
1.28±0.04*
1.07±0.06
0.96±0.05
1.01±0.08
0.91±0.07
0.80±0.09
0.86±0.08
0.75±0.03*
0.83±0.07
0.85±0.08
0.89±0.04
pH
7.15±0.06
7.19±0.05
7.18±0.03
7.15±0.04
0.81±0.05
7.23±0.05
0.89±0.04
7.18±0.02
1.02±0.07
0.98±0.06
1.01±0.04
1.05±0.07
0.98±0.05
0.86±0.04
1.00±0.03
0.97±0.05
1.05+0.11
1.07±0.04
1.03±0.06
absolute. PCr, phosphocreatine;
*p<0.05 compared with control, using Student's t test with Bonferroni's correction for multiple observations.
approximately 10-20% below control was noted;
concomitantly, segment shortening demonstrated an
overshoot to approximately 5-10% above control
(Figure 2, Table 3). This pattern was observed in
seven of the eight pigs studied. End-diastolic and
end-systolic segment lengths were slightly shorter
than control during this period. The overshoot in
segment shortening and the undershoot of Pi per-
TABLE 3. Segment Shortening and Coronary Blood Flow During and Following 24 Seconds of Coronary Occlusion
Cor Q
EDL
ESL
SS
Time (sec)
Occlusion
0-4.8
4.8-9.6
9.6-14.4
14.4-19.2
19.2-24
1.00±0.07
1.02±0.08
1.04±0.08*
1.05±0.08*
1.06±0.08*
1.00+0.09
1.06±0.10*
1.15±0.11*
1.20±0.11*
1.25±0.11*
0.99+0.01
0.84±0.05
0.55±0.09*
0.41±0.09*
0.25±0.09*
0
0
0
0
0
Recovery
2.18±0.20*
0.38±0.09*
2.84±0.21*
0.65±0.08*
2.95±0.22*
0.90±0.06*
2.72±0.23*
1.04±0.04
2.48±0.24*
1.06±0.03
2.25±0.24*
1.07±0.04
2.00+0.21*
0.96+0.07
1.06+0.04
0.95+0.08*
1.80±0.19*
1.06±0.03
33.6-38.4
0.95±0.08*
0.96±0.07
1.68±0.18
1.06±0.04
38.4-43.2
0.95±0.08*
0.96±0.07
1.56±0.20
1.06±0.03
0.94±0.08*
43.2-48
0.96±0.07
1.43±0.17
1.05+0.03
48-52.8
0.95±0.08*
0.96±0.07
1.38±0.15
1.09+0.03
52.8-57.6
0.95±0.08*
0.96±0.07*
1.36±0.14
57.6-62.4
1.08±0.03
0.96±0.07
0.95±0.08*
All values are normalized to their respective controls. EDL, end-diastolic length (mean control, 10.8 mm); ESL, endsystolic length (mean control, 8.7 mm); SS, segment shortening (mean control, 19.3%); Cor Q, coronary blood flow
0-4.8
4.8-9.6
9.6-14.4
14.4-19.2
19.2-24
24-28.8
28.8-33.6
1.06+0.08*
1.04±0.08*
1.01±0.08
0.99±0.07
0.98±0.07
0.97±0.07
1.22±0.11*
1.13±0.10*
1.03±0.09
0.98±0.08
0.96±0.08
0.95±0.08*
velocity.
*p<0.05 compared with control, using Student's t test with Bonferroni's correction for multiple observations.
495
Schwartz et al Dynamic Changes of Myocardial Function and Energy Metabolism
3
- - *
2
0
0
+
0
0
O..
PCr
Pi
ATP
-..
SS
A
....Cor Flow
0
n~~~~~~~~~
.
0
20
40
60
Time (seconds)
FIGURE 2. Changes in phosphorus metabolite peak heights
and systolic segment shortening
during and following 24 seconds
of coronary occlusion. Combined data from eight pigs. Values are normalized to their
respective preocclusion control
levels. Standard errors for the
data are listed in Tables 1 and 2.
Note lack of change of systolic
shortening (SS) or phosphorus
metabolites during the first 4.8
seconds of occlusion, rapid
recovery of SS and metabolites
following occlusion release, and
late undershoot of inorganic
phosphate (Pi). PCr, phosphocreatine; Cor Flow, coronary
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flow.
sisted at the end of the data collection period (62
seconds after occlusion release), but resolved fully
during the 5-minute interval between occlusions.
During occlusion, the dynamic changes in normalized segment shortening exhibited a strong, linear
correlation with those of normalized PCr (slope=2.3,
r2=0.97, SEE=0.06), Pi (slope=-1.1, r2=0.96, SEE=
0.06), 1/Pi (slope= 1.7, r2=0.98, SEE=0.03), and PCr/
Pi (slope=1.2, r2=0.98, SEE=0.05). There was a
poor correlation between changes in segment shortening and ATP (slope=3.8, r2=0.51, SEE=0.25).
These relations are shown in Figure 3. When the data
from individual pigs were analyzed separately, similar
linear relations were found, with average r2 values of
0.84 (segment shortening versus PCr), 0.74 (versus
1/Pi), 0.78 (versus PCr/Pi), and 0.31 (versus ATP).
During the recovery from ischemia, the relations
between segment shortening and PCr and Pi became
curvilinear. At a given level of phosphorus metabolites, segment shortening was greater during the recovery from, as compared with the onset of, ischemia.
Figure 4 and Tables 2 and 3 illustrate the relation
between segment shortening and PCr/Pi. For example,
during the interval 14.4-19.2 seconds of occlusion,
normalized PCr/Pi was 0.51 and normalized segment
shortening was 0.41. During the interval 4.8-9.6 seconds of recovery, PCr/Pi was similar at 0.47, but
segment shortening was considerably greater at 0.65.
Analysis of data from individual pigs revealed a similar
"hysteresis loop" in six of the eight animals. There
were no significant differences in calculated intracellular pH between points on the descending and
ascending limbs of the hysteresis loop.
Discussion
Dynamic Relation Between Contractile Function and
Energy Metabolism
This study demonstrates that pronounced changes
in myocardial contractile function and high-energy
phosphate metabolism occur synchronously during
brief coronary occlusion. With a time resolution of
4.8 seconds, dynamic changes in regional segment
shortening bore a strong, linear relation to concomitant changes in PCr, Pi, and the PCr/Pi ratio. As in all
studies of myocardial function and energy metabolism during ischemia, this investigation cannot prove
a causal relation between variables that change in
parallel. Such proof awaits an experimental intervention that alters the intracellular level of one phosphorus metabolite without producing the other metabolic effects of ischemia. However, the extremely
close temporal correlation between direct measures
of mechanical function and energy metabolism demonstrated in this study is consistent with a causal
relation.
Several mechanisms have been proposed to
explain the impairment of cardiac contractility by
perturbed myocardial energy metabolism during
(I)
to
*
*
0
0
E
a
Pcr/Pi
PCr
1/Pi
ATP
z
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Normalized peak height
FIGURE 3. Relation between systolic segment shortening
(SS) and phosphorus metabolites during 24 seconds of coronary occlusion. Combined data from eight pigs. Time intervals
after release of occlusion are indicated to the left of data. Note
that changes in SS are strongly correlated with those of
phosphocreatine (PCr) (r2=0.97), l/inorganic phosphate (Pi)
(r2=0.99), and PCr/Pi (r2=0.98), but notATP (r2=0.51).
496
Circulation Research Vol 67, No 2, August 1990
1.2 -
recovery
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.
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0.0
0.2
0.4
0.6
0.8
1.0
1.2
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FIGURE 4. Relation between systolic segment shortening (SS) and ratio of phosphocreatine to inorganic phosphate (PCr/
Pi) during and following coronary occlusion.
Combined data from eight pigs. Data are
nornalized to preocclusion control values.
Arrows indicate temporal sense of relation.
Note that at a given level of PCr/Pi, SS is
greater during the recovery than the onset of
ischemia.
1.4
Normalized PCr/Pi
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
ischemia. These include an inhibitory effect of Pi on
myofilament calcium sensitivity,21,22 a depressant
effect of intracellular acidosis23 or lactate,24 or a
reduction in the cytosolic phosphorylation potential
([ATP]/[ADP][P,])25 or free energy of ATP hydrolysis.26 For any of these factors to be considered a
likely regulator of contractile function during ischemia, changes in that factor should occur in advance
of, or simultaneously with, changes in contractility. In
addition, changes in contractile function should be
strongly correlated with changes in the proposed
regulating factor.
Clarke et a19 examined the dynamic relation
between energy metabolism and contractile function
(assessed by rate-pressure product) in isolated, perfused rat hearts during and following 2 minutes of
global ischemia. High-energy phosphate metabolites
and pH were measured by 31P NMR with a 10-second
time resolution. These investigators concluded that
the cytosolic phosphorylation potential controls myocardial contractile function, because this was the only
metabolic parameter to decline at a rate faster than
the rate-pressure product during ischemia. However,
the rate-pressure product is an indirect index of
contractile state, and data from isolated, crystalloidperfused hearts may not fully apply to the regulation
of contractility in the in situ, blood-perfused heart.
In the current experiment, segment shortening was
strongly and synchronously related to changes in
PCr, Pi, and the PCr/Pi ratio (which has been used as
an approximation to the phosphorylation potential27). During the first 4.8 seconds of occlusion, no
changes were detected either in segment shortening
or in any of the phosphorus metabolites. This brief
period of metabolic and functional stability may
reflect the utilization of residual oxygen in capillary
blood or oxygen stored in myocardial myoglobin.28
The decline in segment shortening that occurred
during the remainder of the occlusion period bore a
strong linear relation to the simultaneous changes in
PCr (r2=0.97), Pi (r2=0.96), and PCr/Pi (r2=0.98).
The precise temporal correspondence of these functional and metabolic changes suggests that alterations in high-energy phosphate metabolism rapidly
and directly regulate cardiac contractility at the onset
of myocardial ischemia; however, it must be reemphasized that temporal correspondence is not proof
of a causal relation.
The hypothesis is further supported by a study of
contractile function during steady-state, graded ischemia in the pig, performed in this laboratory.29
Under these disparate experimental conditions, the
relation between segment shortening and PCr/Pi was
nearly identical to that determined in the present
study, suggesting that the same regulatory mechanism was operative. However, because ischemia
causes concomitant changes in several parameters of
energy metabolism, it is difficult to assign the primary
regulatory role to the changes in Pi, the phosphorylation potential, or the free energy of ATP hydrolysis.
In the current study, the marked decline in contractile function during ischemia was accompanied by
small, poorly correlated changes in the f3-ATP resonance. This result corroborates previous findings that
ATP depletion is prevented during brief periods of
ischemia by utilization of PCr via the creatine kinase
reaction.1,7,913
It is also unlikely that intracellular acidosis mediated
the pronounced decline in segment shortening that
occurred during 24 seconds of ischemia. The change in
pH was most likely quite small, because the pH values
calculated from the chemical shift of Pi during ischemia
and early recovery (7.15-7.23, Table 2) are similar to
those determined under nonischemic conditions in
other experimental models.6"19'30'31 In addition, the consumption of protons accompanying the breakdown of
34% of myocardial PCr by the creatine kinase reaction
can be estimated to have raised intramyocardial pH by
0.04 units.3 Other investigators32 have found that intracellular pH actually rises during an initial period of
hypoxia via this mechanism.
Why Is the Relation Between Contractility and
Phosphorus Metabolites Altered During Reactive
Hyperemia?
An important finding of this study is that the
relation between segment shortening and phosphorus metabolites is different during the recovery from
ischemia compared with the onset of ischemia. At a
given level of PCr, Pi, or PCr/Pi ratio, segment
Schwartz et al Dynamic Changes of Myocardial Function and Energy Metabolism
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
shortening was greater during the recovery from
ischemia than during the onset of ischemia. The
relation between segment shortening and phosphorus metabolites is therefore not unique and most
likely reflects a multifactorial regulation of contractility, with changes in another, independent factor
during the recovery from brief ischemia.
This additional independent factor may be the
increased coronary blood flow rate during reactive
hyperemia. In 1963, Gregg'4 described an augmentation of systolic performance and oxygen consumption
resulting from an increase of coronary flow and/or
perfusion pressure to supranormal levels. The Gregg
phenomenon has been demonstrated in experimental
models in which coronary flow is increased by pharmacological vasodilation, without an increase in perfusion pressure.33 The most widely proposed mechanism for the phenomenon is that mechanical
distension of myofibrils by adjacent distended
intramyocardial vessels34,35 leads to increased contractility, perhaps by a localized Frank-Starling
mechanism. An alternative explanation is that a
surfeit of myocardial oxygen delivery leads to
increased oxygen utilization,36 improved energetics
with an increased phosphorylation potential, and
augmented ATP utilization for contractile activity.
In the present study, contractile function during
early reactive hyperemia exceeded that during ischemia, under comparable metabolic conditions (Figure 4). Therefore, the wide, initial portion of the
hysteresis loop cannot be explained by a change in
energetic state, but may reflect a direct augmentation
of contractility by the elevated coronary blood flow of
reactive hyperemia via the Gregg phenomenon. In
addition, the final recovery points in Figure 4 cluster
at a normalized segment shortening value of approximately 1.1 and a normalized PCr/Pi value of approximately 1.2. This overshoot could reflect an augmentation of the phosphorylation potential by excess
myocardial oxygen delivery during reactive hyperemia, with a resultant increase in contractility.
Pagani et a137 also observed an overshoot in contractile function following 1 minute of ischemia in
dogs, which could be abolished by preventing reactive
hyperemic coronary flow from exceeding the control
flow rate. Stahl et a138 found that dipyridamole- or
papaverine-induced hyperemia augmented segment
shortening and shifted the end-systolic pressurelength relation to the left in stunned canine myocardium. While energy metabolism was not assessed in
these studies, the results also support enhancement
of postischemic contractile function by an elevated
coronary blood flow rate.
In the isolated ferret heart, Kihara et a139 recently
found that abnormal intracellular calcium transients
and left ventricular dysfunction produced by ischemia could be partially reversed by hypoxic perfusion. These data suggest that coronary blood flow,
even in the absence of oxygen delivery, may modulate
contractility after ischemia via an effect on calcium
transients.
497
Several alternative explanations for the hysteresis
loop appearance of Figure 4 must be considered. A
macroscopic Frank-Starling mechanism does not
explain the results, because end-diastolic segment
length was not different during ischemia versus
recovery at a given level of PCr/Pi (Table 3). Similarly, calculated intracellular pH was not significantly
different between the two limbs of Figure 4. Lower
levels of lactate (because of washout) during recovery
as compared with the onset of ischemia are unlikely
for two reasons. First, no pH differences are apparent at comparable PCr/Pi levels. Second, the decline
in myocardial lactate during reactive hyperemia has
been shown to be slower than its increase during
brief ischemia in dogs.13 It is possible that autonomic
reflexes, such as activation of baroreceptors by the
small decline in arterial pressure during occlusion,
increased the activity of cardiac sympathetic nerves
during reactive hyperemia, with a consequent
increase in contractility. However, it is unlikely that a
4-7 mm Hg fall in arterial pressure could provoke a
25-45% increase in segment shortening (at a given
PCr/Pi) by sympathetic activation. In the study by
Pagani et al,37 the postischemic overshoot in contractility was not affected by P-blockade with propranolol
or depletion of catecholamine stores with reserpine.
Differences in intramyocardial blood volume
between occlusion and reflow must also be considered in interpreting the data of Figure 4. Enddiastolic intramyocardial blood volume has been estimated to constitute 13% of myocardial mass in
anesthetized dogs, and this percentage may increase
with vasodilation.40 Conversely, when arterial inflow
is occluded, intramyocardial blood volume falls
because of systolic compression of capacitance
vessels.41 Increased intramyocardial blood volume
during reflow, compared with occlusion, could cause
an apparent increase in Pi (and an apparent decrease
in PCr/Pi) because of a larger superimposed signal
from intramyocardial 2,3-DPG. Thus, some of the
hysteresis in Figure 4 could reflect a leftward shift of
the ascending limb because of increased intramyocardial blood volume. It is doubtful, however, that
this is the sole explanation for the hysteresis. A plot
of normalized segment shortening versus normalized
PCr (Figure 5) also exhibits hysteresis, though somewhat less prominently than Figure 4. Because blood
contains no PCr, the hysteresis evident in Figure 5 is
not readily explained by changes in intramyocardial
blood volume.
Finally, changes in left ventricular wall thickness
beneath the surface coil must be considered in
explaining the hysteresis relation of Figures 4 and 5,
since left ventricular wall thickness may vary with
changes in coronary blood flow.42 NMR acquisitions
were gated to end-diastole to minimize the effects of
changing left ventricular wall thickness during and
following ischemia. A change in wall thickness would
reciprocally alter the amount of myocardium and
intracavitary blood contained within the sensitive volume of the coil, possibly affecting the determination of
498
Circulation Research Vol 67, No 2, August 1990
1.2 -
recovery
2
1.0-
_i
control
C')
UI)
0.8-
/
"'i.
10
N
-*-
0.6-
--- *--
E
0
0.4
-
z
19.2-24 sec occlusion
0.2
Occlusion
Reflow
FIGURE 5. Relation between systolic segshortening (SS) and phosphocreatine
(PCr) during and following coronary occlusion. Combined data from eight pigs. See
Figure 4 for explanation.
ment
0.0
0.4
0.6
0.8
1.0
1.2
Normalized PCr
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
metabolite levels. To determine the extent of changes
in end-diastolic wall thickness in this experiment, two
pigs were instrumented with a pair of wall thickness
crystals adjacent to the surface coil. In these pigs,
end-diastolic wall thickness remained between 100%
and 104% of control during all occlusion and recovery
time intervals. Such small changes in end-diastolic
wall thickness are unlikely to have significantly
affected the relations shown in Figures 4 and 5.
Limitations
Metabolic measurements made by 31P NMR. While
31P NMR is a powerful tool for the repetitive, nondestructive assessment of myocardial energy metabolism, it has several important limitations. Because
the sensitive volume of the surface coil includes some
intracavitary ventricular blood, spectral overlap
between 2,3-DPG and Pi is unavoidable. This overlap
reduces the accuracy of Pi peak height and chemical
shift determinations, especially under nonischemic
conditions, when Pi is low. Although the Pi peak was
clearly discernible during ischemia and early recovery, conclusions regarding the role of Pi and pH in
the regulation of contractility must be tempered by
this limitation. 31P NMR cannot provide a direct
measurement of free ADP, one of the determinants
of the phosphorylation potential and the free energy
of ATP hydrolysis. In addition, the interaction
between changes in high-energy phosphate metabolism and intracellular calcium levels cannot be
assessed with this technique.
Regional heterogeneity of metabolic and functional
Both the metabolic and functional
of the myocardium to ischemia may vary
transmurally. Therefore, it is desirable to obtain
these measurements from the same transmural layer
of the left ventricle. NMR techniques capable of
precise spatial localization usually require long data
acquisition times. In the present experiment, such
techniques would have required averaging data from
an inordinately large number of interventions to
achieve the desired temporal resolution with an
acceptable signal-to-noise ratio. However, the subendocardial NMR signal was weighted more heavily
than the subepicardial signal by choosing a pulse
responses.
responses
length that provided maximal sensitivity in the subendocardium. Concomitantly, segment shortening was
measured in the subendocardial layer. On the left
ventricular surface, the ischemic region was large
compared with the area encompassed by the coil and
dimension gauges, making substantial lateral contamination of the NMR signal from nonischemic
myocardium unlikely. Therefore, metabolic and functional correlations should be possible in this experimental model, despite the constraints of spatial heterogeneity.
Effects of anesthesia. Arterial pressure in this group
of pigs was somewhat depressed, especially in those
receiving halothane and sodium pentobarbital. However, the low left ventricular end-diastolic pressures
and normal segment shortening8 suggest peripheral
vasodilation, rather than significant myocardial
depression. In addition, control phosphorus spectra
showed no evidence of metabolic impairment, and
the 300% increase in peak reactive hyperemic flow
implies that coronary vasodilator reserve was far
from exhausted.
The two pigs anesthetized with chloralose demonstrated similar responses during ischemia to those of
the pigs anesthetized with halothane and pentobarbital (nadir segment shortening, 31% of control;
nadir PCr, 66% of control; peak Pi, 184% of control;
segment shortening versus PCr, r=0.81; segment
shortening versus Pi, r= -0.81). In addition, both
chloralose-anesthetized pigs demonstrated "hysteresis" in these relations during recovery. These data
suggest that the results of the current study do not
depend strongly on the type of anesthetic used.
Summary
Numerous previous studies have supported the
regulation of myocardial contractile function during
ischemia by changes in high-energy phosphate
metabolism, based on measurements made under
steady-state or slowly changing conditions. However,
the most pronounced changes in both contractile
function and energy metabolism occur early in ischemia. In this study, a precise temporal correspondence was demonstrated between changes in contractile function and PCr, Pi, and PCr/Pi in the in situ
Schwartz et al Dynamic Changes of Myocardial Function and Energy Metabolism
pig heart subjected to brief coronary occlusion. These
data strongly support a direct regulatory relation
between high-energy phosphate metabolism and contractile function during ischemia. During reactive
hyperemia, increased coronary blood flow may independently augment contractility.
This study also demonstrates that high temporal
resolution NMR data can be obtained in a large,
intact animal preparation at moderate field strength,
with spectral reconstruction from multiple, reproducible interventions.
Acknowledgments
We sincerely thank Gerald Matson, PhD; Donald
Twieg, PhD; Mr. James Buchanan; and Alexander
Smekal, MD; for technical advice and assistance.
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KEY WORDS * energy metabolism * contractility * reactive
hyperemia * magnetic resonance spectroscopy
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Dynamic relation between myocardial contractility and energy metabolism during and
following brief coronary occlusion in the pig.
G G Schwartz, S Schaefer, D J Meyerhoff, J Gober, P Fochler, B Massie and M W Weiner
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Circ Res. 1990;67:490-500
doi: 10.1161/01.RES.67.2.490
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1990 American Heart Association, Inc. All rights reserved.
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