(Circulation. 1999;100:1540-1547.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Acute Right Ventricular Restrictive Physiology After Repair of Tetralogy of Fallot
Association With Myocardial Injury and Oxidative Stress
From the Departments of Paediatric Cardiology (R.R.C., J.B., A.N.R.), Cardiac Surgery (D.F.S., C.L.), Anaesthesia and Intensive Care (S.M., A.P., J.M.G.G.), and Clinical Biochemistry (M.K., J.H.), Royal Brompton Hospital, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK.
Correspondence to Andrew N. Redington, Cardiothoracic Unit, Great Ormond Street Hospital, Great Ormond Street, London, W1N 3JH, UK. E-mail reding{at}ibm.net
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Abstract |
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Background—Acute right ventricular (RV) restrictive physiology after tetralogy of Fallot repair results in low cardiac output and a prolonged stay in the intensive care unit (ICU). However, its mechanism remains uncertain.
Methods and Results—In the first 24 hours after tetralogy of Fallot repair (n=11 patients), serial prospective measurements were performed of cardiac troponin T, indexes of NO production (NO2- and NO3- combined as NOx), and iron metabolism and antioxidants. RV diastolic function was assessed by transthoracic Doppler echocardiography. Patients who had a long stay in the ICU were characterized by restrictive RV physiology (nonrestrictive group [n=7]: 3.0±0.6 days [mean±SD]; restrictive group [n=4]: 10.7±3.1 days). Troponin T peak concentration and the area under its concentration-time curve (AUC) were higher in the restrictive RV group (peak: restrictive group 17.0±2.8 µg/L, nonrestrictive group 10.4±4.6 µg/L, P<0.03; AUC: restrictive group 268.8±73.6 µg · h-1 · L-1, nonrestrictive group 136.2±48.3 µg · h-1 · L-1, P<0.03). Plasma NOx/creatinine concentrations were higher in the restrictive group than the nonrestrictive group at 2 hours after bypass (restrictive group 1.3±0.4, nonrestrictive group 0.8±0.2; P=0.04) but were similar by 24 hours. Iron loading peaked 2 to 10 hours after bypass and was more severe in the restrictive group (peak transferrin saturation: restrictive group 83.9±13.0%, nonrestrictive group 58.3±16.2%, P=0.05; minimum total iron-binding capacity: restrictive group 0.59±0.21%, nonrestrictive group 0.76±0.06%, P=0.04; minimum iron-binding antioxidant activity to oxyorganic radicals: restrictive group 9.5±22.4%, nonrestrictive group 50.6±11.4%, P=0.01).
Conclusions—After tetralogy of Fallot repair, acute restrictive RV physiology is associated with greater intraoperative myocardial injury and postoperative oxidative stress with severe iron loading of transferrin.
Key Words: tetralogy of Fallot • ventricles • diastole • free radicals
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Introduction |
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After tetralogy of Fallot repair in late infancy or early childhood, the majority of children have an uneventful postoperative course, with an intensive care unit (ICU) stay of 2 to 3 days and early mortality of <1% in the best series.1 A subgroup of patients have a distinctly different course characterized by low cardiac output necessitating prolonged ventilation, inotropic support, and intensive care for 7 to 10 days. These patients were previously demonstrated to have acute right ventricular (RV) restrictive physiology, characterized by antegrade late diastolic flow in the pulmonary artery; ie, atrial contraction is transmitted to the pulmonary artery, and the stiff RV acts as a passive conduit with little or no true RV filling during this period of diastole.2 This is a transient phenomenon that is resolved within 2 weeks, coincident with clinical improvement.2 3 The origin of acute RV restriction is unknown. Intraoperatively, the tetralogy of Fallot RV may be inadequately protected,4 5 because its anterior position makes satisfactory hypothermia difficult,6 and hypertrophy complicates the homogeneous delivery of cardioplegia. Despite these considerations, previous studies2 3 have failed to demonstrate a relationship between acute RV restriction and simple measures of the intraoperative insult, such as duration of cardiopulmonary bypass or ischemia.
The chronic hypoxemia of cyanotic heart disease results in a downregulation of antioxidant defenses,7 making cells vulnerable to oxidant damage from the sudden increase in oxygen concentration at the time of surgical repair.8 9 In vivo oxygen-derived free radical generation is critically dependent on iron being available for catalysis,10 but normally this redox active iron is tightly sequestered in macromolecular complexes. Cyanosed patients with high hemoglobin concentrations are vulnerable to cardiopulmonary bypass–induced hemolysis that releases free hemoglobin11 and low-molecular-weight iron, and in addition, redox active transition metals (iron and copper) are known to be mobilized after cardiac ischemia.12 The toxicity of the superoxide radical that may be liberated by this process is potentiated by a reaction with NO to form peroxynitrite, which is deleterious in its own right but can also form the extremely damaging hydroxyl radical.13 Even in the absence of these reactions, NO may have a negative inotropic effect on the heart.14
Hence, patients with tetralogy of Fallot were prospectively studied to investigate the relationship between myocardial injury, oxidative stress due to increased iron concentrations and NO production over the first 24 postoperative hours, and the subsequent development of acute RV restrictive physiology.
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Methods |
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The protocol was approved by the Royal Brompton Hospital Clinical Research Ethics Committee, and parents of all subjects (Table 1
) provided informed consent. Only
patient 11 had previously received a shunt. Patients fasted for 12
hours before surgery, and only infusions of saline or dextrose
solutions and human albumin replacement were given until the
end of the study. No patient was given intravenous
nutritional support, drug therapy, or vasoactive agents known to
contain or be metabolized to nitrate compounds. Cold crystalloid
cardioplegia (St Thomas' solution 1) was administered via the
aorta. The mode of repair was uniform: ventricular septal
defect closure was transatrial; a small right ventriculotomy was made
in all patients; 3 patients required a transannular patch, and the
remainder received only an outflow tract patch. Arterial
samples were taken before bypass, 5 minutes after the onset of bypass,
5 minutes after removal of the cross-clamp, and 5 minutes after
cardiopulmonary bypass was terminated. Subsequent sampling was
at 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours after bypass. All blood
samples were kept on ice, and the plasma fraction was obtained 15
minutes after sampling (4000 rpm [gav
1735] at 4°C for 10 minutes).
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Nitrite and Nitrate Measurement
NOx is the sum of nitrite
(NO2-) and nitrate
(NO3-) anions. All utensils
used for the NOx samples were washed with MilliQ (pure) water
before use. Plasma was stored at -70°C. NOx was measured by
capillary electrophoresis (Oxonon) as
NO2- and
NO3-.15
Cardiac Troponin T
Troponin T was measured by ELISAs (ELISA troponin T,
Boehringer Mannheim).16 17
Indexes of Iron Metabolism
The details of our measurements of iron metabolism
have been reported elsewhere.18 19 Total plasma
protein was determined with a kit assay (Sigma) based on the Lowry
technique. Plasma transferrin was measured by radial immunodiffusion
with a polyclonal antibody to pure standards of human apotransferrin
(Behring-Hoechst). Total plasma iron and iron-binding capacity were
measured with a kit assay (Sigma) based on the ferrozine
spectrophotometric technique. Transferrin saturation was derived from
the measured total iron-binding capacity and was found to be in close
agreement with values calculated from the amount of transferrin
present.
Low-molecular-mass bleomycin-chelatable iron was determined as previously described.18 Briefly, the reaction mixture contained DNA, bleomycin, and the test plasma buffered to pH 7.4 with a Tris salt. On addition of ascorbate, bleomycin chelates iron from the test plasma and degrades DNA. Malondialdehyde is released from deoxyribose and reacts with 2-thiobarbituric acid to form a chromogen that is measured spectrophotometrically.
Iron-binding antioxidant protection is an assay of plasma antioxidant activity based on the ability of transferrin to bind iron and hence inhibit iron-catalyzed free radical reactions. The iron-binding antioxidant activity of test plasma was measured in 2 different oxidizing systems, one that generated an organic oxygen radical (phospholipid peroxidation)18 and the other an oxo-iron species (bleomycin-iron damage to DNA).19 In both these assays, the ability of the subject's plasma to inhibit oxidation is expressed as a percentage inhibition relative to the control sample (not containing plasma) to which 100% damage occurs.
Acquisition of Echocardiograms
Echocardiograms were acquired 24 to 28 hours after surgery by
use of our previously described method.2 Briefly, imaging
was performed with a Hewlett-Packard Sonos 1500 with
simultaneous ECG, phonocardiogram, and respiratory motion
recording. Pulmonary arterial
systolic and diastolic Doppler characteristics
were acquired with the pulsed Doppler sample volume placed at the
midpoint between the pulmonary valve leaflets and bifurcation.
Patients were divided into 2 groups, those with and those without
Doppler evidence of restrictive RV diastolic
physiology.
Data Analysis
Summary measures (maximum or minimum value and area under the
concentration-time curve [AUC]) were used to analyze serial
data, and the AUC was obtained by the trapezium rule.20
Comparisons between the restrictive and nonrestrictive groups were by
the Mann-Whitney U test and Fisher's exact test for
proportions. The null hypothesis was rejected if
P<0.05.
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Results |
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Demographic data and clinical outcomes are presented in Table 1
. No patient had residual RV outflow tract obstruction
(Doppler gradient >30 mm Hg). There was a bimodal
distribution of ICU stay, with all patients with prolonged ICU stay
being characterized by the presence of restrictive RV
physiology.2 Although cardiopulmonary bypass and
ischemic times tended to be longer in the restrictive group,
they were not statistically different from the nonrestrictive group,
and this was previously confirmed in 2 larger series of
patients.2 21
Myocardial Injury
Arterial troponin T was undetectable before
cross-clamp release, after which it rose rapidly and remained elevated
for the duration of the study (Figure 1). Peak troponin T and the AUC
were significantly higher in the restrictive group than in the
nonrestrictive group (Table 2).
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NO Metabolites
Arterial NOx fell with the onset of bypass and
remained at this trough level until 6 to 10 hours after bypass, when it
slowly began to rise (Figure 2). Graphic
inspection showed that the restrictive and nonrestrictive groups had
almost identical profiles, except that the curve for the restrictive
group had a parallel upward shift, and in this small group of patients,
the CIs between the 2 groups overlapped. The higher preoperative NOx
concentration in the restrictive group seems largely responsible for
this shift, but it remains unexplained; it was not attributable to
differences in renal function, hemoglobin concentration, or degree of
cyanosis. In fasted patients in the absence of exogenous NOx
administration, the NOx concentration-time series reflect, albeit
indirectly, endogenous NOx
production.22 23 24 Cardiopulmonary bypass
increases the extracellular fluid volume, and because the volume of
distribution of NOx approximates the extracellular fluid
volume,22 23 any increase in NOx concentration implies an
increase in production and/or decrease in elimination rates for
NOx. NOx undergo renal elimination, and during the 2- to 24-hour
postbypass period, there were only mild alterations in overall renal
function, as estimated from changes in plasma creatinine,
and importantly, no significant differences between the 2 groups
(nonrestrictive group: 58.8±43.3%; restrictive group: 84.5±41.1%;
P=0.20). NOx was normalized to plasma creatinine
to account for differences in renal function,25 26
and at 2 hours after bypass, the NOx/creatinine ratio
(Table 2) was higher in the patients with restrictive physiology
(P=0.04).
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Iron Metabolism
The initiation of cardiopulmonary bypass produced the
expected fall in total plasma protein (Figure 3) with a subsequent slow rise. There was
a related fall in total iron-binding capacity (Figure 4) and transferrin concentration (not
shown but analogous to Figure 3). However, whereas total
protein returned to prebypass concentrations by 24 hours after bypass,
the total iron-binding capacity and transferrin concentration remained
depressed. Concurrent with this fall in iron-binding proteins was a
rise in total serum iron, which initially rose immediately on going
onto bypass but was subsequently followed by a further and greater rise
at 2 to 10 hours (Figure 5). This
resulted in iron loading of transferrin and elevated transferrin
saturations (Figure 6) in both
groups, but these were higher in the restrictive group, with the
majority (3 of 4 patients) exceeding 80%, whereas this occurred in
only 1 of 7 of the nonrestrictive patients (patient 3).
Bleomycin-chelatable iron was detected in only 1 patient between 4 and
10 hours after bypass (Figure 7), who
subsequently developed severe restrictive physiology, and did not occur
in any of the nonrestrictive patients. Bleomycin cannot chelate iron
from ferritin, transferrin, and heme-containing proteins, and
bleomycin-chelatable iron is thought to be a low-molecular-weight iron
that is catalytically active.
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Plasma antioxidant activity was assayed in terms of the ability
of the plasma to bind iron and inhibit formation of oxo-iron species
(Figure 8) or oxyorganic radicals (Figure 9). The restrictive group had severely
depressed plasma antioxidant activity compared with the nonrestrictive
group, demonstrated by the minimum for the inhibition of oxo-organic
radical formation (9.5±22.4%; P=0.01). Indeed, in both
these assays of iron-binding antioxidant activity, at 
1 time point, 2
of the restrictive patients consistently had plasma that
stimulated rather than inhibited oxidative reactions.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Acute RV restrictive physiology after tetralogy of Fallot repair results in a prolonged stay in the ICU2 and is associated with greater intraoperative myocardial injury followed by postoperative oxidative stress in the form of severe iron loading of transferrin.
Myocardial Injury
Although RV restrictive physiology is a transient
phenomenon,2 3 our patients had clear evidence of greater
intraoperative myocardial injury and presumably myocyte loss. The
restrictive group had both higher troponin T peak and higher AUC values
than the nonrestrictive group, and indeed, the peak values in the
restrictive group were in the extreme end of the range found in a
previous pediatric series of patients undergoing open-heart surgery in
our16 17 and other27 institutions. In
addition, the peak troponin T values for patients with restrictive
physiology were 3 to 4 times higher than previously reported values for
adults undergoing coronary artery surgery28 29 or
heart transplantation30 and lie in the upper range
reported for adults with myocardial infarction.31
NO Metabolites
The NOx/creatinine ratio at 2 hours after bypass was
higher in the restrictive group (P=0.04), although this
difference was absent 24 hours after bypass. This may reflect higher NO
levels in the early reperfusion period in the restrictive group. In
addition to its direct negative inotropic effect on cardiac muscle at
high concentrations,14 NO may contribute to oxidative
damage by releasing iron from ferritin32 and exacerbating
free radical–mediated injury.33 Two previous
studies34 35 reported a perioperative NOx
profile in children undergoing repair of tetralogy of Fallot that is
consistent with our results. Although both had fewer tetralogy
patients than the present study, NOx was found to fall with the
onset of bypass, and similar to our findings, one study34
showed there was a subsequent rise.
Iron Overload
The acute-phase response to systemic inflammation includes a fall
in total iron-binding capacity and transferrin that has been attributed
to extravasation of these proteins.36 This was previously
demonstrated in noncyanotic children undergoing atrial septal defect
closure, a much shorter open-heart operation, in whom there
was a decrease in absolute transferrin levels and a fall in transferrin
saturation.37
Our cohort of tetralogy patients developed a pattern of iron overload
superimposed on this acute-phase response. Initially with the onset of
bypass, there was a fall in total plasma proteins (Figure 3),
total iron-binding capacity (Figure 4), and transferrin (not
shown, but analogous to Figure 3), with a raised total serum
iron (Figure 5) and transferrin saturation (Figure 6).
This early iron loading was followed by a more severe period of iron
loading between 2 and 10 hours after bypass, characterized by elevated
levels of transferrin saturation and total serum iron as well as
decreased total iron-binding capacity (Table 2). The saturation
of transferrin with iron in the restrictive group increased by 150% to
200%, levels that were extremely high compared with normal values in
children of comparable age (restrictive group 83.9±13.0%;
nonrestrictive group 58.3±16.2%; normal 5th to 95th centile range:
10% to 47%38 ). This degree of iron overload was
functionally significant, because it depleted antioxidant activity in 2
assays that assessed the ability of the plasma to inhibit formation of
oxo-organic radicals and oxo-iron species.18 19 The
restrictive group as a whole exhibited diminished antioxidant activity
in the oxy-organic radical assay compared with the nonrestrictive
group, and half of the restrictive group had frankly pro-oxidant
plasma. Furthermore, 1 patient in the restrictive group had a
measurable level of bleomycin-chelatable iron. This is the most severe
manifestation of iron loading and represents a
low-molecular-weight iron that is redox active and can function as a
Fenton reagent to catalyze hydroxyl radical formation.10
This redox active iron is particularly important because the tetralogy
of Fallot myocardium has diminished antioxidant defenses
and is vulnerable to free radical–mediated injury.4 5 7
There are multiple potential sources for this iron loading, eg,
bypass-related hemolysis, mobilization of tissue iron into the vascular
compartment after ischemia,12 and
cardiomyocyte necrosis liberating myoglobin and other
intracellular proteins containing iron.
Plasma antioxidant depletion, as measured by 2 assays different from those used in the present study, has previously been shown early after bypass in children undergoing open-heart surgery.39 Several of these children were found to have pro-oxidant plasma, and the authors speculated that a Fenton reagent might be present, a phenomenon confirmed by our data.
Implications for Long-Term RV Function
Two syndromes of RV restrictive physiology in patients with
tetralogy of Fallot have been described: an acute syndrome in the
immediate postoperative period2 and a late syndrome whose
clinical manifestation is delayed by years.40 41 Although
acute RV restriction initially resolves within 
14 days, a recent
study21 demonstrated these patients were at increased risk
of subsequently developing late RV restriction and that acute RV
restriction was the only independent predictor of late restriction.
This late RV restriction, presumed to reflect a stiffer RV that allows
less pulmonary regurgitation, has been
demonstrated to result in a smaller heart, improved exercise tolerance,
and decreased risk of ventricular
arrhythmia.40 41
This study has demonstrated that during tetralogy of Fallot repair, some children experience severe myocardial injury. Peak troponin T levels in some were equivalent to those of an adult with a massive myocardial infarction, although this clearly represents more diffuse injury than that seen with coronary occlusion. Results from animal and clinical studies42 have suggested that myocardial ischemia and infarction are followed by a reparative response that involves fibrous tissue deposition, even at sites remote from the original lesion. Increased collagen turnover has been demonstrated in adults after myocardial infarction.43 A similar mechanism may be present in our patient population, ie, those with the greatest intraoperative global myocardial injury subsequently develop the greatest fibrotic response, which later manifests as a noncompliant RV with echocardiographic evidence of restrictive physiology.
Conclusions
Patients destined to develop acute RV diastolic
dysfunction with restrictive physiology and long ICU stays after
tetralogy of Fallot repair suffer more intraoperative myocardial injury
and subsequent oxidative stress related to increased iron
concentrations. These observations provide novel insights into the
mechanism of transient postoperative ventricular
dysfunction and form the basis for future studies.
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Acknowledgments |
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Dr Gutteridge and Sharon Mumby would like to thank the British Lung Foundation and the British Heart Foundation for their generous research support. The authors would also like to thank Julia Peatling for her assistance in the preparation of this manuscript.
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Footnotes |
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Dr Chaturvedi is currently at the Department of Cardiology, Children's Hospital, Boston, Mass.
Received February 5, 1999; revision received June 15, 1999; accepted June 23, 1999.
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