Vol. 281, Issue 6, H2446-H2455, December 2001
Postischemic functional recovery in immature hearts
is influenced by performance index and assessment technique
Shona M.
Torrance and
Carin
Wittnich
Clinical Science Division, Department of Surgery/Physiology, and
Institute of Medical Science, University of Toronto, Toronto M5S
1A8; and Division of Cardiovascular Surgery, The Hospital for Sick
Children, Toronto M5G 1X8, Ontario, Canada
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ABSTRACT |
In the
in vivo immature heart, conflicting results are reported for
postischemic functional recovery. This study determines whether
interpretations of functional recovery are influenced by the
contractile performance index (systolic pressure, developed pressure,
and maximum rate of systolic pressure increase per unit time) reported
or the assessment technique (isovolumetric and variable-volume)
utilized. In neonatal pigs (n = 6) on cardiopulmonary bypass, each performance index was examined using both assessment techniques before myocardial ischemia and at 15, 30, and 60 min of reperfusion. With the use of the isovolumetric technique, all performance indexes had significantly different recovery. With the use
of the variable-volume assessment technique, recovery of systolic
pressure was significantly better than the other indexes. When recovery
was compared between the two assessment techniques, systolic pressure
recovered significantly better when assessed using the variable-volume
technique. For each performance index, the correlation between
isovolumetric and variable-volume techniques was positive before
ischemia but negative during reperfusion, suggesting that the
assessment techniques identified conflicting postischemic
contractile performances. Thus both the contractile performance index
reported and the assessment technique employed are ultimately important
in interpreting postischemic functional recovery in the
immature heart.
preload-dependent performance; preload-independent performance; performance indexes; ventricular function; ischemia-reperfusion
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INTRODUCTION |
CONTROVERSY PERSISTS
regarding the immature heart's potential for postischemic
recovery of contractile performance. Although many studies report
moderate postischemic functional recovery, some studies have
identified recovery above 85% (1, 11, 28, 30) or below
30% (23, 30, 36). The use of different contractile performance indexes and assessment techniques could contribute to these
conflicting findings. For instance, various studies report contractile
performance indexes, including peak systolic pressure (9, 10, 12,
15, 20, 23, 35, 36), developed pressure (1, 13, 15, 17,
23, 28, 30, 32, 36), systolic pressure-rate product (10,
20), and maximum rate of systolic pressure increase per unit
time (+dP/dtmax) (1, 8, 10, 12, 13, 17,
23, 36), but rarely examine more than one or two of these
indexes simultaneously. Interestingly, studies (23, 36)
that examined two indexes found that peak systolic pressure had two- to
threefold greater postischemic functional recovery than either
developed pressure or +dP/dtmax. This suggests that contractile performance indexes may vary in their susceptibility to ischemic injury. One focus of this study was to
simultaneously examine postischemic recovery of three different
contractile performance indexes to compare their sensitivity to
ischemia-reperfusion in the immature heart.
In the immature heart, myocardial performance is frequently assessed in
animal studies using fixed-preload assessment techniques. For example,
in the isolated immature heart, common fixed-preload assessment
techniques include the working Langendorff model with fixed left atrial
pressure (11, 12, 20, 23, 36) or isovolumetric intraventricular balloon (1, 2, 8, 13, 15, 17, 29, 30,
32). These techniques are also commonly used to examine the
functional response of the immature heart to stresses such as
ischemia (1, 2, 8, 13, 15, 17, 29, 30, 32). In
contrast, variable-volume performance assessment techniques, generated
by incrementally increasing the end-diastolic volume and determining
the intraventricular pressure-volume relationship, are more frequently
reported in adult hearts and rarely reported in the immature heart
(9, 10). In addition, many aspects of contractile
performance are highly sensitive to sarcomere length or ventricular
volume (3, 21, 24). Thus isovolumetric and variable-volume
performance assessment techniques examine different aspects of
myocardial contractile performance, which could yield conflicting
results and contribute to existing controversies in the literature.
Thus the second focus of this study was to simultaneously examine
myocardial performance using both isovolumetric and variable-volume assessment techniques to determine whether they provide quantitatively different information about postischemic recovery of
contractile performance in the immature heart. To achieve these two
goals, this study assesses and compares left ventricular (LV) function, as measured by three commonly reported contractile performance indexes
(systolic pressure, developed pressure, and
+dP/dtmax), in the same in vivo immature hearts
using both isovolumetric and variable-volume performance assessment
techniques both before ischemia and during postischemic reperfusion.
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MATERIALS AND METHODS |
Preparation.
Immature male Yorkshire pigs (3 days old, n = 6) were
anesthetized with an intraperitoneal injection of pentobarbital sodium (65 mg/kg), intubated, and mechanically ventilated with medical air. A
catheter was inserted into the right carotid artery and advanced to the
aortic arch to monitor arterial blood pressure. Another catheter was
inserted into the right jugular vein and advanced to the superior vena
cava to monitor central venous pressure. These catheters were connected
to pressure transducers (COBE; Lakewood, CO) and a physiological
recorder (BIOPAC Systems; Goleta, CA). Arterial blood samples were
obtained, and appropriate adjustments were made to ensure normal
physiological values for the arterial partial pressures of oxygen
(PaO2) and carbon dioxide (PaCO2) as
well as HCO
and pH (ABL30 Acid-Base Analyzer,
Radiometer; Copenhagen, Denmark).
After sternotomy and systemic heparinization (400 IU/kg heparin
sulfate), piglets were placed on normoxic normothermic cardiopulmonary bypass (CPB) using a Sarns 9000 Perfusion System (3M Sarns; Ann Arbor,
MI). Appropriate adjustments maintained both mean arterial blood
pressure (61 ± 1 mmHg) and central venous pressure (< 2 mmHg).
The CPB perfusion circuit was primed with fresh porcine blood, gas
exchange was via a "Minimax" membrane oxygenator (Medtronic; Anaheim, CA), and gas flows were adjusted to maintain normal
physiological blood gases (PaO2 and
PaCO2). Heparin was administered to maintain an
activated clotting time >500 s, sodium bicarbonate was administered to
maintain pH (7.40 ± 0.02), and pentobarbital sodium was
administered to ensure a surgical plane of anesthesia. Many studies
(23, 29, 32, 36) that examined myocardial performance
utilizes an in vitro, Langendorff, crystalloid-perfused model.
Extrapolation of results from these studies to the in vivo heart may
not be valid because blood provides a more physiological environment than crystalloid perfusate (14, 30), and the perfusion
medium itself reportedly influences postischemic functional
recovery (30). Therefore, the current study employed a
stable in vivo whole blood CPB model in which physiological and
hemodynamic parameters were monitored (Table
1) and maintained throughout the study. By utilizing whole blood at normal physiological hematocrit, blood gases, and temperature, this study provides more physiologically relevant information about postischemic recovery of contractile performance in the in vivo immature heart.
Myocardial performance assessment.
To assess myocardial performance, a compliant fluid-filled latex
balloon was inserted into the LV and attached to a pressure transducer
using polyethylene tubing. Heart rate as well as peak systolic
pressure, peak diastolic pressure, and developed (systolic 
diastolic) pressure were obtained directly from the original pressure
trace. This pressure trace was electronically differentiated with
respect to time, and the peak positive deflection
(+dP/dtmax) was utilized as a measure of
contractility. In this study, myocardial function was determined by
both isovolumetric (fixed balloon volume) and variable-volume
(pressure-volume relationship) assessment techniques. The absolute
values for each contractile performance index (systolic pressure,
developed pressure, and +dP/dtmax) and diastolic
pressure were recorded for each balloon volume at each study interval.
For isovolumetric assessment, fluid was injected into the balloon to
establish a fixed end-diastolic volume. The balloon volume used was
that which initially produced normal physiological ventricular peak
systolic and diastolic blood pressure. Thus balloon volume varied for
each heart depending on its size and the animal's normal LV pressures.
For each heart, once this volume was determined during baseline
preischemic assessment, the same volume was used throughout the experiment.
For variable-volume assessment, fluid was incrementally injected into
the balloon to progressively increase the end-diastolic volume. During
the initial baseline assessment, this volume ranged from 0.1 ml to a
maximum of 2 ml but did not exceed an LV peak diastolic pressure of 10 mmHg. After this original set of data was obtained, the developed
pressure-vs.-volume relationship was generated to assess the
appropriateness of this volume range. If there were several data points
beyond the linear portion of this curve (higher volume), the maximum
volume for all subsequent performance assessments was reduced
accordingly. For each heart, once the appropriate volume range was
determined during this initial assessment, this same volume range was
used to generate performance index-vs.-volume curves at each study
interval (baseline and reperfusion). Ultimately, the absolute values
for each contractile performance index (systolic pressure, developed
pressure, and +dP/dtmax) and diastolic pressure
were recorded for each volume, thus generating a performance
index-vs.-volume relationship. Several of these indexes have complex
preload-dependent modulation, but variable-volume performance was
quantified and expressed as the slope of the linear portion of this
performance index-vs.-volume relationship.
Experimental protocol.
After CPB was established, stable baseline isovolumetric and
variable-volume myocardial performance data were obtained for each
heart (n = 6) before ischemia. An aortic cross
clamp (AXC) was then applied just above the aortic valve to initiate
global myocardial ischemia. Normothermia was maintained
throughout the ischemic interval. Immediately after AXC
placement, the LV balloon was filled to generate a pressure of 10 mmHg.
The time to ischemic contracture onset (pressure increase of 2 mmHg in the balloon) was measured and recorded for each heart. After
the ischemic contracture onset was reached (33.3 ± 3.1 min), the fluid was withdrawn from the balloon, the AXC was removed,
reperfusion was initiated, and the "isovolumetric volume" was
reinjected into the balloon. Repeat isovolumetric and variable-volume
performances were assessed at 15, 30, and 60 min of reperfusion.
Myocardial contracture can be associated with cell swelling, edema, and
capillary collapse or compression (18, 19), all of which
potentially impede coronary reperfusion (4, 18, 19, 22).
For each heart in this study, reperfusion was confirmed by coronary
distension and the return of normal arterialized color. Although
coronary flow might have varied somewhat between hearts, both
isovolumetric and variable-volume performances were assessed in the
same hearts; thus any differences in recovery between assessment techniques would not be due to differences in coronary perfusion.
After 60 min of reperfusion, CPB was terminated, and the animals were
euthanized by pentobarbital overdose. All experimental procedures and
protocols used in this investigation were reviewed and approved by the
University of Toronto Animal Care and Use Committee and are in
accordance with the National Institutes of Health Guide for the
Care and Use of Laboratory Animals (NIH Publication No. 96-03, Revised 1996) and the Canadian Council on Animal Care guidelines.
Data analysis.
In all study animals, the absolute value for each performance index was
determined in each heart using both assessment techniques. The
"baseline" value for each performance index was the mean value obtained from multiple baseline performance assessments conducted before ischemia. At each reperfusion interval, the absolute
value for each performance index was again determined, but
postischemic recovery of each contractile performance index was
also expressed as a percentage of the baseline value. All three time
points were used to calculate the mean percent recovery throughout
reperfusion. Paired t-test (31) was used to
analyze both differences in recovery between contractile performance
indexes within each assessment technique and differences in
recovery of each performance index between assessment techniques. To
further explore the relationship between performance assessment
techniques for individual hearts, the correlation between isovolumetric
and variable-volume assessment techniques was determined and quantified
using the Pearson correlation coefficient (31).
Correlation analysis before ischemia (baseline) was performed
on the absolute data, whereas correlation analysis during reperfusion
was performed on both the absolute data and the percent recovery data
for all three reperfusion intervals. Positive correlations indicate
that isovolumetric and variable-volume assessment techniques had a
direct relationship and would yield consistent conclusions. In
contrast, no correlation indicates dissociation between the assessment
techniques, whereas negative correlation indicates that these two
performance assessment techniques had an inverse relationship and thus
would yield contradictory findings. Values are expressed as means ± SE. Statistical trends were accepted for 0.05 < P
< 0.10, and statistical significance was accepted at
P < 0.05 (31).
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RESULTS |
Model perfusion parameters and baseline myocardial performance.
Arterial blood gases, acid-base parameters (PaO2,
oxygen saturation, PaCO2, pH, HCO,
and base excess), and hemodynamic parameters (mean arterial pressure
and heart rate) were monitored during ventilation before CPB and were maintained within these limits throughout CPB (Table 1). These data
confirm that this normothermic normoxic CPB model provided normal
physiological and hemodynamic parameters. The absolute baseline values
for systolic pressure, developed pressure, and +dP/dtmax, as well as diastolic pressure,
obtained using both the isovolumetric (Table
2) and variable-volume assessment
techniques (Table 3), are shown. The
negative baseline isovolumetric diastolic pressures obtained in this
experiment are consistent with other animal preparations (5,
27) as well as a study (25) in humans undergoing
mitral valvuloplasty. These studies all generated conditions of LV
volume clamping; thus the negative ventricular pressures produced by
the restoring forces of titin (16) became apparent under
these experimental conditions. The other baseline isovolumetric
performance data are consistent with similar animal models and confirm
appropriate baseline physiological performance, whereas the
variable-volume performance data delineate the corresponding variable-volume performance. Tables 2 and 3 also contain the absolute
performance data at 15, 30, and 60 min of reperfusion.
Comparison of postischemic recovery between contractile
performance indexes within each assessment technique.
Postischemic recovery of systolic pressure, developed pressure,
and +dP/dtmax was assessed by both isovolumetric
and variable-volume performance assessment techniques. Although the
focus of this study is myocardial contractile performance, the
diastolic component of myocardial performance may be important for
interpretation and thus is also reported. After
ischemia-reperfusion, these hearts had an increase of 5.4 ± 0.4 mmHg in the isovolumetric diastolic pressure and an increase of
5.3 ± 0.7 mmHg/ml in the slope of the diastolic
pressure-vs.-volume relationship. Thus, in this study, these immature
hearts had evidence of quantitatively similar moderate diastolic
dysfunction with ischemia-reperfusion. Postischemic myocardial contractile performance was examined in the setting of
this moderate diastolic dysfunction. Differences in recovery between
contractile performance indexes using the isovolumetric (Fig.
1) and variable-volume (Fig.
2) assessment techniques are both shown.
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Fig. 1.
Differences in postischemic recovery between
contractile performance indexes using the isovolumetric assessment
technique. A: systolic vs. developed pressure; B:
systolic pressure vs. maximum rate of systolic pressure increase per
unit time (+dP/dtmax); C: developed
pressure vs. +dP/dtmax. The data shown include
the individual data points for each heart at 15 ( ), 30 ( ), and 60 min ( ) of reperfusion, the
overall means ± SE for each performance index, and the
P values for the paired t-test.
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Fig. 2.
Differences in postischemic recovery between
contractile performance indexes using the variable-volume assessment
technique. A: systolic vs. developed pressure; B:
systolic pressure vs. +dP/dtmax; C:
developed pressure vs. +dP/dtmax. The data shown
include the individual data points for each heart at 15 (), 30 (), and 60 min
() of reperfusion, the overall means ± SE for
each performance index, and the P values for the paired
t-test.
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With the use of the isovolumetric technique, the 72% recovery of
systolic pressure was significantly and consistently greater than the
67% recovery of developed pressure (Fig. 1A;
P < 0.0001) but had a trend to worse recovery than
+dP/dtmax (Fig. 1B; 77%, P = 0.08). It is interesting to note that hearts with
the best recovery of systolic pressure had consistently better recovery of +dP/dtmax, whereas hearts with poor recovery
of systolic pressure had highly variable recovery of
+dP/dtmax. The 67% recovery of developed
pressure was also significantly lower than the 77% recovery of
+dP/dtmax (Fig. 1C; P = 0.0015); however, the magnitude of this difference was also dependent
on the level of recovery. Specifically, hearts with the best recovery
of developed pressure had over 20% higher recovery of
+dP/dtmax, but hearts with poor recovery of developed pressure had similar or only slightly better recovery of
+dP/dtmax.
With the use of the variable-volume assessment technique, the 88%
recovery of systolic pressure was significantly (P < 0.0001) higher than recovery of both developed pressure (Fig.
2A; 65%) and +dP/dtmax (Fig.
2B; 62%). Interestingly, the magnitude of this difference
in recovery was also variable. For instance, hearts with the greatest
recovery of systolic pressure had <10% worse recovery of the other
indexes, whereas hearts with poor recovery of systolic pressure had as
much as 40% lower recovery of developed pressure and
+dP/dtmax. Finally, recovery of developed
pressure (65%) and +dP/dtmax (62%) were not
statistically different (Fig. 2C). Thus, within each
assessment technique, the extent of postischemic recovery is
determined by the performance index examined.
Comparison of postischemic recovery of each contractile
performance index between assessment techniques.
Differences in postischemic recovery of each contractile
performance index between the isovolumetric and variable-volume
assessment techniques were also examined. Specifically, recovery of
systolic pressure was 15% lower using the isovolumetric compared with
the variable-volume assessment technique (Fig.
3A; P = 0.02).
In contrast, recovery of developed pressure was not different between
the two assessment techniques (Fig. 3B). Additionally,
although it did not achieve statistical significance, recovery of
+dP/dtmax was 15% higher using the
isovolumetric compared with the variable-volume assessment technique
(Fig. 3C; P = 0.12). Thus
postischemic recovery of contractile performance is also
influenced by the assessment technique utilized.
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Fig. 3.
Comparison of postischemic recovery of each
contractile performance index between the isovolumetric (solid bars)
and variable-volume (open bars) assessment techniques. A:
systolic pressure; B: developed pressure; C:
+dP/dtmax. Values are means ± SE
(percentage of baseline). P values for the paired
t-test are shown.
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Although these data examine overall performance index- and assessment
technique-specific differences, they do not address the relationship
between isovolumetric and variable-volume assessment techniques within
the same heart. This relationship can be most accurately assessed by
determining the correlation between isovolumetric and variable-volume
assessment techniques. Before ischemia (baseline), all three
contractile performance indexes produced relatively strong positive
correlations between isovolumetric and variable-volume assessment
techniques. These correlations were statistically significant and
quantitatively similar for systolic pressure (Fig.
4A; r = 0.77, P = 0.04) and developed pressure (Fig. 4B;
r = 0.78, P = 0.04), whereas
+dP/dtmax yielded a weaker statistical trend
(Fig. 4C; r = 0.68, P = 0.09). Generally, under baseline conditions, isovolumetric and
variable-volume assessment techniques yielded consistent findings for
each contractile performance index. With reperfusion after moderate
ischemic injury, the significant positive correlations
previously identified for all three contractile performance indexes
were lost. The absolute data during reperfusion did not yield
significant correlations for systolic pressure (Fig.
5A; r = 0.39, P = 0.11), developed pressure (Fig. 5B;
r = 0.14, P = 0.59), or
+dP/dtmax (Fig. 5C; r = 0.23, P = 0.36). Interestingly, one animal had
substantially higher baseline performance than all other animals. When
the three data points contributed by this outlier animal were removed
from the analysis of the absolute data during reperfusion, all
three contractile performance indexes yielded negative correlations of
varying strength. This shift to a negative correlation with
ischemia-reperfusion was confirmed when the reperfusion data
for all animals, including the animal with high baseline performance,
were expressed as a percentage of baseline. Specifically, hearts had
similar significant negative correlations for postischemic
recovery of systolic pressure (Fig. 6A; r = 0.52, P = 0.03) and developed pressure (Fig.
6B; r = 0.53, P = 0.02),
whereas +dP/dtmax yielded a highly significant strong negative correlation (Fig. 6C; r = 0.76, P = 0.0002). Interestingly, the outlier animal
identified by examining the absolute data had a percent recovery of
performance consistent with all other animals. Thus, after
ischemia-reperfusion, the strong positive correlations between
isovolumetric and variable-volume assessment techniques for all three
contractile performance indexes were lost and actually became negative.
This suggests that isovolumetric and variable-volume assessment
techniques could yield contradictory findings about recovery after
moderate ischemic injury.
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Fig. 4.
The baseline correlation before ischemia between
absolute values for contractile performance indexes in individual
hearts using isovolumetric vs. variable-volume assessment techniques.
A: systolic pressure; B: developed pressure;
C: +dP/dtmax. The equations of these
relationships are as follows: systolic pressure, y = 0.31x + 1.08; developed pressure, y = 0.31x 4.95; and +dP/dtmax,
y = 0.32x 15.29. The correlation
coefficients (r) and P values are shown.
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Fig. 5.
The correlation during postischemic reperfusion
between absolute values for contractile performance indexes in
individual hearts using isovolumetric vs. variable-volume assessment
techniques. A: systolic pressure; B: developed
pressure; C: +dP/dtmax. The data
shown include the individual data points for each heart at 15 (), 30 (), and 60 min
() of reperfusion, the correlation coefficients, and
P values. The outlier animal (open symbols) is also
identified.
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Fig. 6.
The correlation between postischemic recovery of
contractile performance indexes in individual hearts using
isovolumetric vs. variable-volume assessment techniques. A:
systolic pressure; B: developed pressure; C:
+dP/dtmax. Values are shown at 15 (), 30 (), and 60 min
() of reperfusion. The outlier animal is also
identified (open symbols). The correlation coefficients and
P values are shown, and the equations of these relationships
are as follows: systolic pressure, y = 0.54x + 126.88; developed pressure, y = 0.70x + 112.70; and
+dP/dtmax, y = 0.57x + 106.51.
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DISCUSSION |
Over the past few years, studies have examined
postischemic functional recovery in the immature heart.
Although most clinical studies document moderate to severe
postoperative myocardial dysfunction (6, 7) and low output
syndrome (8a) after repair of congenital heart defects, many studies
(1, 11, 15, 28) in experimental animals report minimal
postischemic functional impairment. Because most clinical
outcomes reflect preload-dependent myocardial performance assessment,
whereas most experimental studies utilize preload-independent assessment techniques, these contradictory conclusions could be due to
study-specific differences in the performance assessment techniques
examined. Although the fetal heart has limited preload-dependent modulation of ventricular output (33), the immature heart
has more extensive, but not yet fully developed, preload-dependent modulation of contractile performance. Isovolumetric assessment techniques examine the functional response of the heart to a
fixed ventricular volume and only examine preload-independent aspects of ventricular performance, whereas variable-volume assessment techniques examine the functional response of the heart to a specific range of ventricular volumes (variable preload), which explores both
preload-dependent and preload-independent performance modulation. Thus
variable-volume performance assessment techniques could provide more
physiologically relevant information than those obtained by
isovolumetric analysis alone. Despite this knowledge, experimental studies in immature hearts primarily utilize isovolumetric, not variable-volume, assessment techniques.
In addition, because each performance index (systolic pressure,
developed pressure, and +dP/dtmax) depends on
different cellular mechanisms, which have different susceptibility to
ischemic injury, each performance index potentially yields a
different magnitude of postischemic dysfunction. For example,
using the isovolumetric assessment technique, the reduction in systolic
pressure is consistent with the 60% elevation in lactate content
observed in these hearts (34), which would indicate the
presence of intracellular acidosis. In addition, the 23% reduction in
+dP/dtmax was much more variable but generally
less than that seen in either systolic (28%) or developed pressure
(33%). The reduced postischemic recovery of +dP/dtmax observed in these hearts was likely
due to the combined effects of the 25% reduction in ATP levels
(34) and intracellular acidosis, which would reduce myosin
ATPase activity. The current study confirmed that each contractile
performance index and assessment technique yielded different degrees of
postischemic dysfunction and that isovolumetric and
variable-volume assessment techniques yielded contradictory findings
about postischemic recovery of contractile performance. Thus
both the performance index and the assessment technique must be
considered when interpreting functional recovery in the immature heart.
Isovolumetric vs. variable-volume assessment techniques.
The importance of the assessment technique itself was investigated by
determining whether postischemic recovery of each performance index was quantitatively different when assessed using isovolumetric and variable-volume techniques. Interestingly, recovery of systolic pressure was significantly lower using the isovolumetric compared with
the variable-volume assessment technique. Thus despite the overall
longer sarcomere length for myofilament deactivation that was
identified by the isovolumetric technique, preload-dependent modulation
of myofilament deactivation was maintained with
ischemia-reperfusion. In contrast, postischemic
recovery of developed pressure was quantitatively similar using both
the isovolumetric and variable-volume assessment techniques, suggesting
quantitatively similar injury to preload-dependent and
preload-independent mechanisms. Finally, postischemic recovery of +dP/dtmax was 15% worse using the
variable-volume assessment technique, indicating that there was more
extensive injury to the preload-dependent mechanisms that regulate
+dP/dtmax.
The precise relationship between isovolumetric and variable-volume
assessment techniques is best investigated by analyzing the correlation
using data from individual hearts. At baseline, systolic pressure,
developed pressure, and +dP/dtmax all produced positive correlations between isovolumetric and variable-volume assessment techniques. This indicates that these two assessment techniques would yield consistent findings in the unstressed immature heart. These same hearts were then reperfused after moderate
ischemic injury, and the previously identified significant
positive correlations were lost. In fact, when expressed as a
percentage of baseline, all three contractile performance indexes
yielded negative correlations during reperfusion. This suggests that
the isovolumetric and variable-volume assessment techniques would yield
contradictory conclusions about postischemic functional
recovery and could yield paradoxical conclusions about the
susceptibility to ischemic injury. For example, hearts that had
poor postischemic functional recovery using the isovolumetric assessment technique likely had reduced peak cytosolic Ca2+
levels during systole. It is interesting to note that these hearts also
had the highest functional recovery using the variable-volume assessment technique, indicating that they maintained sarcoplasmic reticulum Ca2+-handling capacity and preload-dependent
regulation of myofilament Ca2+ sensitivity and troponin C
Ca2+ affinity. These hearts would be most capable of
responding to varying loading conditions, and thus would likely
maintain heart function in vivo. In contrast, hearts that exhibited
good recovery using the isovolumetric assessment technique likely had
higher cytosolic Ca2+ levels and had optimal troponin C
Ca2+ binding and myofilament Ca2+ sensitivity
at fixed ventricular volume. However, these hearts also had poor
recovery using the variable-volume assessment technique, indicating
that they had impaired preload-dependent performance regulation. This
likely occurred due to impaired sarcoplasmic reticulum Ca2+
handling, which would profoundly compromise troponin C Ca2+
binding and preload-dependent modulation of myofilament
Ca2+ sensitivity. These hearts would be unable to
adequately respond to varying loading conditions, and thus would be
less able to sustain heart function in vivo.
In summary, in the in vivo immature pig heart, both the contractile
performance index reported and the assessment technique employed are
ultimately important in interpreting postischemic functional
recovery. With the use of the isovolumetric technique, postischemic recovery of all three performance indexes were
significantly different. With the use of the variable-volume technique,
systolic pressure had significantly higher recovery then either
developed pressure or +dP/dtmax. When recovery
between the two assessment techniques was compared, systolic pressure
recovered significantly better with the variable-volume assessment
technique. In addition, the positive correlation between isovolumetric
and variable-volume assessment techniques before ischemia was
lost entirely during reperfusion and even became negative when
expressed as percent recovery. This indicates that the two assessment
techniques would yield contradictory conclusions about
postischemic functional recovery and could yield paradoxical
conclusions about the susceptibility to ischemic injury. Thus
both the contractile performance index and the assessment technique are
ultimately important in interpreting postischemic functional
recovery in the in vivo immature heart.
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ACKNOWLEDGEMENTS |
The authors acknowledge W. J. Wallen, M. P. Belanger, and
C. E. Carlyle for technical expertise and Dr. P. St. Louis
(Clinical Chemist), Department of Clinical Biochemistry, The Hospital
for Sick Children (Toronto) for assistance. This work was made possible by 3M Sarns' generous loan of the Sarns 9000 Perfusion System.
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FOOTNOTES |
We also acknowledge Bach Simpson Ltd. and Ethicon Ltd. for generous
contributions to this research. Grant funding was provided by Heart & Stroke Foundation of Ontario Grant T4181, and S. M. Torrance was
supported by a Research Fellowship from the Ontario Ministry of Health.
Address for reprint requests and other correspondence: C. Wittnich, Univ. of Toronto, Clinical Sciences Div., Medical Sciences Bldg., Rm. 7256, Toronto, ON M5S 1A8 Canada (E-mail:
c.wittnich{at}utoronto.ca).
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 23 November 1999; accepted in final form 7 August 2001.
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