(Circulation. 2000;101:541.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Soluble Complement Receptor-1 Protects Heart, Lung, and Cardiac Myofilament Function From Cardiopulmonary Bypass Damage
From the Departments of Surgery (P.J.C., D.M.C., G.Q., J.J., R.M.U.) and Pediatrics, Division of Pediatric Cardiology (R.N., A.E.O., S.P.S., P.A.W.A.), Duke University, Durham, NC.
Correspondence to Page A.W. Anderson, MD, DUMC, Box 3218, Durham, NC 27710. E-mail ander005{at}mc.duke.edu
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Abstract |
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Background—Host defense system activation occurs with cardiopulmonary bypass (CPB) and is thought to contribute to the pathophysiological consequences of CPB. Complement inhibition effects on the post-CPB syndrome were tested with soluble complement receptor-1 (sCR1).
Methods and Results—Twenty neonatal pigs (weight 1.8 to 2.8 kg)
were randomized to control and sCR1-treated groups. LV pressure and
volume, left atrial pressure, pulmonary artery pressure and
flow, and respiratory system compliance and resistance were measured.
Preload recruitable stroke work, isovolumic diastolic
relaxation time constant (
), and pulmonary vascular
resistance were determined. Pre-CPB measures were not statistically
significantly different between the 2 groups. After CPB, preload
recruitable stroke work was significantly higher in the sCR1 group
(n=5, 46.8±3.2x103 vs n=6, 34.3±3.7x103
erg/cm3, P=0.042); was significantly
lower in the sCR1 group (26.4±1.5, 42.4±6.6 ms,
P=0.003); pulmonary vascular resistance was
significantly lower in the sCR1 group (5860±1360 vs 12 170±1200
dyn · s/cm5, P=0.009);
arterial PO2 in 100%
FIO2 was significantly higher in the sCR1 group
(406±63 vs 148±33 mm Hg, P=0.01); lung
compliance and airway resistance did not differ significantly. The
post-CPB Hill coefficient of atrial myocardium was higher
in the sCR1 group (2.88±0.29 vs 1.88±0.16,
P=0.023).
Conclusions—sCR1 meaningfully moderates the post-CPB syndrome, supporting the hypothesis that complement activation contributes to this syndrome.
Key Words: cardiopulmonary bypass • diastole • myofilaments • calcium
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Introduction |
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Cardiopulmonary bypass (CPB) and its associated strategies are essential for supporting and protecting the patient during cardiac surgery. However, their use has pathophysiological consequences, including prolonged postsurgical recovery and death.1 2 3 CPB activation of inflammatory host defenses, including the complement cascade, has been proposed as a cause of this post-CPB syndrome.1 2 Complement cascade products have been correlated with post-CPB organ dysfunction.1 2
Complement receptor-1 (CR1) inhibits both C3 and C5 convertases of the classical and alternative complement cascade.4 Recombinant soluble CR1 (sCR1) effectively blocks complement activation in vitro and in vivo.5 6 7 We tested the effects of sCR1 on neonatal pig post-CPB ventricular and pulmonary function in vivo because CPB affects the neonatal human and pig similarly6 8 9 10 and sCR1 blocks complement activation in the young pig.6
We found that sCR1 attenuated the deleterious effects of CPB on pulmonary and cardiac function. The effect on left ventricular (LV) function may be a consequence of the preservation of the myofilament’s sensitivity to calcium. These results suggest that sCR1 will protect the human infant exposed to CPB and that complement activation plays an important role in the post-CPB syndrome.
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Methods |
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Twenty neonatal (1-week-old) pigs weighing 1.8 to 2.8 kg (mean 2.4 kg) were randomly assigned to either a control or an experimental sCR1-treated group. All animals received humane care in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23, revised 1985) and as approved by the Duke University Institutional Animal Care and Use Committee. sCR1 (lot No. TP 1097003) was provided by Dr Henry Marsh of Avant Immunotherapeutics.
Surgical Procedure
The neonatal pig was anesthetized (20 mg/kg
ketamine IM, 1 mg/kg acepromazine IM) and mechanically
ventilated (Sechrist Infant Ventilator, model IV-100B, Sechrist
Industries, Inc). A femoral arterial line and
nasopharyngeal temperature probe (Yellow Springs Instrument Co,
YSI-400) were placed. Anesthesia was maintained with
fentanyl (100 µg/kg initial bolus and 50 µg ·
kg-1 · h-1
continuous infusion). The ventilator provided a positive inspiratory
pressure of 25 mm Hg and positive end-expiratory pressure of
3 mm Hg. A pneumotachometer (System 2600 Pediatric
Pulmonary Cart, SensorMedics Corp) was placed in the
ventilation circuit. Respiratory rate and inspired oxygen fraction were
titrated to maintain an arterial
PCO2 of 35 to 45 mm Hg and
PO2 of 100 to 250 mm Hg. Sodium
bicarbonate (8.5%, 10 to 15 mL) was used to maintain a base excess
between -3 and 3 mmol/L. Methylprednisolone (25 mg/kg), given
routinely to infants undergoing CPB in our institution, was given
intravenously before CPB.
After a sternotomy was preformed, umbilical tape was placed around the superior vena cava and inferior vena cava and a 10-mm ultrasonic flow probe was placed around the main pulmonary artery (Transonic Systems Inc).
Ultrasonic crystals were sewn to the LV epicardium in the major and minor axes. Micromanometers (3F, Millar Instruments, Inc) were placed in the pulmonary artery, left atrium, and LV. The tip of the right atrial appendage and the LV apex were excised for in vitro experiments and protein characterization (see below).
Cardiopulmonary Bypass
Neonatal pigs in the sCR1 group were given sCR1 (10 mg/kg IV)
before cannulation. Animals were given heparin (500 IU/kg), and
arterial and venous cannulas (DLP, Inc) were placed. CPB
was initiated 5 to 10 minutes after sCR1 infusion. The CPB circuit
consisted of a Stockert Shiley roller pump (Shiley Inc model
10–10-00), Medtronic Minimax Plus oxygenator (Medtronic Inc), and
Bio-Cal 370 heat exchanger (Bio-Medicus) to maintain piglet temperature
at 37°C. The pump was primed with lactated Ringer’s solution and
fresh donor pig blood to maintain a circuit hematocrit of 18% to 22%.
CPB flow rate was 100 mL · kg-1 ·
min-1, and mean systemic arterial
pressure was maintained at 50 to 60 mm Hg. The pigs were
maintained on CPB for 90 minutes and then separated from CPB without
the use of inotropic agents. Heparin was not reversed.
Data Acquisition
Before administration of sCR1 and after CPB, the blood gases
were stabilized within the above limits (Surgical Procedures). LV
pressure, left atrial pressure, pulmonary arterial
pressure, right ventricular output, LV dimensions,
arterial blood gases, heart rate, nasopharyngeal
temperature, static pulmonary compliance, mean airway
resistance, and systemic arterial blood pressure were
recorded before CPB and at 5 minutes after CPB.10 Data
were also recorded 30 and 60 minutes after CPB. Pressure and flow
data were collected for 8 seconds (sampling rate, 500 Hz) in the
presence of 3 mm Hg continuous positive airway pressure. Data for
calculation of preload recruitable stroke work (PRSW) were collected
for 16 seconds (sampling rate, 200 Hz) with gradual occlusion of the
superior vena cava and inferior vena cava and a continuous
positive airway pressure of 3 mm Hg.
At the completion of the in vivo experiment, right atrial and LV tissues were obtained to assess myofilament sensitivity to calcium and to examine the myofilament proteins (see below).
Data Analysis
Data were acquired and analyzed with software developed
in-house. Pulmonary vascular resistance (PVR) was calculated.
LV end-diastolic volume was obtained from the
sonomicrometric data with the use of an ellipsoid
model.11 12 PRSW was calculated as the slope of the LV
end-diastolic volume-stroke work relation,
end-diastolic volume being varied by vena caval occlusion
as described above.11 12 Stroke work was calculated as the
area of the LV pressure-volume loop.11 12 The time
constant of LV pressure decay during isovolumetric relaxation (;
References 13 and 1413 14 ) was determined by fitting a single exponential
function to the pressure waveform beginning at the minimum of the first
derivative of LV pressure by nonlinear regression.
Isolated Muscle Studies
Preparations
The heart was washed in calcium-free
physiological solution, then placed in skinning
solution (relaxing solution with 0.5% Triton X-100 added) for 30
minutes at 4°C.15 After CPB we used free-running atrial
trabeculae (n=12). The preparations had diameters of 70 to
300 µm (median 150 µm) and lengths of 0.5 to 2.8 mm
(median 1.1 mm).
Solutions
Relaxing (pCa 9.0) and activating (pCa 4.5) solutions were
prepared with the use of 10 mmol/L EGTA as a calcium buffer and
30 mmol/BES as a pH buffer. The compositions of the solutions were
calculated with the use of a computer program16 17 to give
an ionic strength of 190 mmol/L, pMg 3.14, pMgATP 2.50 at pH 7.10,
22.0°C.15 The stability constants were from Reference
1818 . The apparent stability constant used for Ca-EGTA, adjusted for
ionic strength and temperature,19 was
3.702x106 per mol.
The muscle bundle was placed in the cuvette of a Guth apparatus15 and illuminated with a He-Ne laser. Where first-order maxima of the diffraction pattern were discerned, the sarcomere length was set at 2.6 µm. Preparations whose first-order diffraction maxima were not discernible were stretched to what was judged to be a comparable amount.
The preparation was superfused with each of 12 test solutions (22°C, range pCa 8.0 to 4.75) until a steady-state force response was obtained (1 to 2 minutes). The force was recorded on disk using Digidata 1200 data acquisition system and Clampex software (Axon Instruments, Inc). A reading at pCa 8.0 was taken after every 3 or 4 measurements of active force to ascertain stability and provide a baseline for determining active force development. The preparation was then placed in sample buffer for SDS-PAGE and Western blot analysis (see below, Reference 2020 ).
Data Analysis
The force versus free calcium data were fitted with the Hill
equation:
F=Fmax/(1+[K/Ca]nH),
where Fmax is the force at saturating calcium, K
is the free calcium concentration at which
F/Fmax=0.5, and nH is the
Hill coefficient;
pCa50=-log10(K). The fit
was carried out with the use of nonlinear least squares
(Statgraphics-Plus version 7, Statistical Graphics Corp).
Muscle Proteins
The myocardial proteins were resolved with the use of
SDS-PAGE.20 Western blots were probed with cardiac
troponin I (TnI)- and troponin T (TnT)-specific
antibodies.21 22
Statistical Analysis
Values are given as mean±SEM unless indicated otherwise.
Results were considered statistically significant at a value of
P
0.05. Unless stated otherwise, we used ANCOVA, with
pre-CPB values used as the covariate, to compare results obtained 5
minutes after CPB from the control and sCR1 groups. Where necessary to
meet the assumptions underlying the statistical tests, appropriate
transformation of the data (the reciprocal of compliance and the
squared reciprocal of ) or nonparametric significance
tests (Wilcoxon’s rank sum test for the Hill coefficient) were
used. Means and standard errors are shown for the original
(untransformed) data. Statistical analysis was carried out
using R (version 0.63) computer software.23
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Results |
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Animals Studied
Eleven animals fulfilled the criteria for acceptance in the study. The following animals were excluded: 1 control animal died before CPB, 4 (2 control and 2 sCR1-treated) could not be separated from CPB, 1 sCR1-treated animal had persistent respiratory acidosis after CPB, and 1 control animal was hypothermic after CPB. Two other animals were excluded because of equipment failure: The blood gas machine malfunctioned for 1 sCR1-treated animal and the physiological data for 1 control animal were lost.
In Vivo Data
The pre-CPB values of the measured and computed variables were
not significantly different (see Table 1
). We used the data collected
5 minutes after CPB for determining the effect of sCR1 on the in
vivo measures (Tables 1 and 2).
Pre-CPB and post-CPB results as a function of time are shown in Figure 1.
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) and sCR1
(•) groups. Data were obtained before CPB and 5, 30, and 60 minutes
after CPB. The positive effects of sCR1 on these measures gradually
decreased. Data are shown as mean±SEM; asterisk indicates
statistically significant difference between data from 5 minutes after
CPB (see Table 2
Preload Recruitable Stroke Work
Pre-CPB baseline PRSW (combined mean for both groups) was
63.0±6.6x103 erg/cm3.
Post-CPB PRSW was significantly higher in the sCR1 group than in the
control group: 46.8±3.2x103
erg/cm3, n=5, versus
34.3±3.7x103 erg/cm3, n=6
(P=0.042, see Table 2
). Heart rates were similar in
the 2 groups: 157±9 for sCR1, 165±9 for controls (P=0.54).
During the 60 minutes after CPB, mean PRSW in the control group
increased gradually, but the sCR1 group did not change (Figure 1).
Time Constant of Isovolumic Relaxation
Baseline pre-CPB combined mean for was 25.5±1.5 ms. Post-CPB
means were 26.4±1.5 ms for the sCR1 group and 42.4±6.6 ms for the
control group (P=0.003, Table 2), which indicated
that sCR1 prevented CPB-induced slowing of ventricular
relaxation. Heart rates did not differ significantly between the 2
groups (155±8 sCR1, 163±9 controls, P=0.51). Over the 60
minutes after CPB, in the sCR1 group increased slightly (see Figure 1).
PVR and Oxygenation
The pre-CPB baseline PVR (combined mean for PVR) was 2720±400
dyn · s/cm5. Post-CPB PVR was
significantly lower in the sCR1 group: 5860±1360 vs 12 170±1200
dyn · s/cm5 (P=0.009, Table 2). After CPB, the arterial
PO2 in 100%
FIO2 was significantly higher in
the sCR1 group (406±63 vs 148±33 mm Hg, P=0.01).
Figure 1 illustrates PVR as a function of time after
CPB.
Pulmonary Mechanics
Pre-CPB pulmonary compliance (combined mean) was
3.09±0.23 mL/cm H2O. Post-CPB compliance
adjusted means obtained by ANCOVA were 1.94
mL/cm H2O for the sCR1 group and 1.60
mL/cm H2O for the control group
(P=0.16). Pre-CPB and post-CPB respiratory resistance did
not differ significantly (P=0.19, Table 2).
In Vitro Data
Sensitivity of Myofilaments to Calcium
Post-CPB pCa50 did not differ between the 2
groups (6.08±0.05, n=5 sCR1, vs 6.09±0.05, n=7 control,
P=0.83, Table 3), but the Hill
coefficient (nH) was significantly higher in the
sCR1 group: 2.88±0.29 versus 1.88±0.16 (P=0.023, Table 3 and Figure 2). The higher nH suggests
that sCR1 is effective in maintaining myofilament function in
myocardium exposed to CPB.
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Myofilament Proteins
The profiles of the myofilament proteins in atrial and
ventricular myocardium from control and
sCR1-treated groups demonstrated in pre-CPB and post-CPB specimens a
single band of TnI with the same electrophoretic mobility (Figure 3), indicating no difference in
cAMP-dependent phosphorylation21 and no
TnI proteolysis (Figure 3). Small amounts of a TnT proteolytic
product were evident in post-CPB ventricular
myocardium from 4 control and 3 sCR1-treated animals (see
Figure 3).
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Discussion |
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In the human neonate, the post-CPB syndrome is both frequent and severe. Clinically important generalized edema, abnormal lung compliance, and impaired LV filling affect up to 50% of infants undergoing CPB.2 3 24 The mechanisms underlying the pathophysiological consequences of CPB remain to be established. CPB activates the host defense cascades.1 2 3 The complement products increase vascular permeability, smooth muscle contraction, neutrophil activation, and cytosolic calcium concentration, leading to pathophysiological effects similar to those seen after CPB.1 2 25 26
The classical and alternative complement pathways are inhibited by the membrane-bound CR1 and sCR1.4 Recombinant sCR1 blocks activation of both complement pathways in vivo and in vitro,5 decreases postischemia myocardial damage,5 and moderates CPB-associated increase in PVR.6 We used recombinant sCR1 in the neonatal pig to test the effect of blocking CPB-induced complement activation on heart and lung function.
Myocardial contraction and relaxation depend, among other things, on the instantaneous concentration of cytosolic calcium and on myofilament sensitivity to calcium. Myocardial ischemia alters these regulators of contraction.27 28 29 To minimize the likelihood of ischemia and reperfusion injury, the CPB strategy used in this study included neither circulatory arrest nor aortic cross-clamp. Although our flow rates were similar to those used clinically, our use of normothermia may have resulted in decreased energy stores. The interaction of all these effects could alter both systolic and diastolic function.
Diastolic Function
The time constant of isovolumic diastolic relaxation,
, has been used in the piglet and other animals as a measure of
diastolic function.13 30 Pigs exposed to CPB
and deep hypothermic circulatory arrest showed evidence of slower
ventricular relaxation.30 Our CPB study, which
did not include hypothermic circulatory arrest, also showed a post-CPB
increase in in the controls, which suggests that CPB itself is a
contributor to this increase. In a study of human neonates, we found
that many had acquired diastolic dysfunction after CPB
(measured by reversal of mitral diastolic
inflow24 ). In vitro exposure of isolated myocytes to
hyperkalemia and hypothermia to mimic aspects of CPB
strategies resulted in decreased cell shortening and relaxation
rate.31 The relation of these changes in the myocyte to
the in vivo effects of CPB remains to be established.
Systolic Function
PRSW has been used previously to characterize the decrease in LV
systolic function (contractility) in the
neonatal pig exposed to bypass10 because it is little
affected by changes in loading conditions.11 12 The
decrease in systolic function observed in our control piglets
is similar in magnitude to that described previously.10 In
contrast, in our study of post-CPB human neonates, we found abnormal
systolic function.24 The apparent discrepancy is
probably caused by inotropic agents being administered to all the
infants but not to the pigs. Additionally, the
echocardiographically derived ejection fraction used in
the infants is more sensitive to alterations in loading than is PRSW.
Whatever the basis, our results showed post-CPB depression of
ventricular systolic function. However, mean PRSW
was significantly higher in the sCR1 animals, which suggests that sCR1
has a useful role in maintaining systolic function in hearts
exposed to CPB.
Myofilament Function and Structure
Function
We used chemically skinned myocardial preparations to measure the
sensitivity of the myofilaments to calcium: the relation between free
calcium concentration and force (Reference 3232 , Figure 2) in
terms of pCa50 (the pCa at half the force
generated under a saturating calcium concentration) and
nH (a measure of the slope of the relation
between force and pCa). Alterations in the myofilaments’ sensitivity
to calcium can cause altered ventricular function. For
example, ß-tropomyosin overexpression increases the sensitivity of
the myofilaments to calcium in vitro as measured by
pCa50 and results in slower diastolic
relaxation in vivo.33
nH was higher in the sCR1 group than in the
controls (Figure 2). In the absence of a shift in the
pCa50, a smaller nH would
be expected to result in a lower rate of diastolic
relaxation. Our finding in the post-CPB sCR1 group of a higher
nH and faster isovolumic ventricular
relaxation is consistent with the effect of sCR1 in maintaining
normal interaction between the myofilaments and calcium and preserving
ventricular diastolic function.
Protein Structure
We examined the myofilament proteins with the use of SDS-PAGE and
Western blot analysis to search for possible mechanisms
underlying the deleterious effects of CPB and the protective effects of
sCRl. We were unable to demonstrate a difference in TnT proteolysis of
post-CPB myocardium between the 2 groups, making it
unlikely that proteolysis of myofilament proteins was a significant
factor in the effects of sCR1 on post-CPB ventricular
function in our piglets.
Pulmonary Function
CPB in the neonatal human and pig affects pulmonary
function.1 2 3 6 8 24 In our previous study of the effects
of CPB on the neonatal human, ventricular
diastolic and pulmonary dysfunction in affected
infants contributed to post-CPB morbidity,24 tripling the
duration of mechanical ventilation after surgery. The significantly
higher arterial PO2 after
CPB in the sCR1 animals suggests that sCR1 protects lung function.
Gillinov et al6 reported, in young pigs, that after CPB,
PVR increased by 338% in control but only by 147% in sCR1-treated
animals. Our results from neonatal pigs show very similar results:
After CPB, PVR increased by 350% and 120% in the control and sCR1
groups, respectively.
Summary
This study demonstrates that sCR1 protects the
myocardium and lungs from some of the deleterious effects
of CPB. A greater effect is seen early after CPB. Given that sCR1 is a
specific inhibitor of complement activation, our results
support the hypothesis that complement activation is an important
contributor to the post-CPB syndrome. The protection by sCR1 of
ventricular diastolic function appears to be
based, at least in part, on preservation of myofilament cooperativity
at the sarcomere level. The decrease in the
pathophysiological consequences of CPB in pigs that
have received sCR1 suggests that sCR1 may be useful in decreasing the
effects of CPB on the infant.
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Acknowledgments |
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This study was supported in part by the National Institutes of Heath (grants HL-42250 and HL-20749) and the Children’s Heart Foundation. We thank Avant Immunotherapeutics and Dr Henry Marsh for the sCR1.
Received April 27, 1999; revision received August 6, 1999; accepted August 16, 1999.
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