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Ann Thorac Surg 1996;62:553-558
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Thrombomodulin and Angiotensin-Converting Enzyme Activity During Pediatric Open Heart Operations

Vascular Biology and Pharmacology Unit, Institute of Child Health, London, England

Accepted for publication April 12, 1996.

	Abstract

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background. Thrombomodulin and angiotensin-converting enzyme are endothelial glycoproteins. The metabolism of these substances is altered when endothelial cells are damaged.

Methods. Serum thrombomodulin level was assayed in 56 children and angiotensin-converting enzyme activity determined in 27 children with congenital heart disease before, during, and after open heart operations.

Results. The thrombomodulin level was significantly higher in children with a high pulmonary blood flow who had pulmonary hypertension than in those with a normal pressure (p < 0.01), and although all patients showed an increase in serum thrombomodulin after coming off cardiopulmonary bypass, the increase was greater in those with preoperative pulmonary hypertension (p < 0.05). Serum angiotensin-converting enzyme activity was normal preoperatively in all children, irrespective of pulmonary arterial pressure, and decreased in all after coming off cardiopulmonary bypass but decreased to a significantly greater extent in those who had pulmonary hypertension preoperatively (p < 0.05).

Conclusions. These findings are compatible with the presence of pulmonary endothelial cell injury and dysfunction before intracardiac repair, which is exacerbated by cardiopulmonary bypass.

	Introduction

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Cardiopulmonary bypass (CPB) elicits a generalized vascular inflammatory response, which is thought to be due to the interaction of activated leukocytes and endothelial cells. The lung is particularly vulnerable in children with congenital heart disease associated with a high pulmonary blood flow [1]. The postoperative course can be complicated by the postperfusion syndrome more frequently in these than in other patients, and the pulmonary vasculature is labile [2, 3]. Other evidence of endothelial dysfunction includes preoperative and intraoperative abnormalities in eicosanoid biosynthesis and an elevated postoperative plasma endothelin level caused partly by a reduction in pulmonary extraction of this peptide [4].

Thrombomodulin and angiotensin-converting enzyme (ACE) are endothelial glycoproteins. When endothelial cells are damaged, the metabolism of these substances is altered [5–7]. Thrombomodulin is released in excessive amounts when the endothelium is injured in vivo and in vitro [5, 6]. Recent reports suggest that the serum thrombomodulin concentration is a reliable marker of acute vascular endothelial injury [8, 9]. Angiotensin-converting enzyme is a membrane-bound glycoprotein located in endothelial pinocytic vesicles [7]. The main source of ACE activity is thought to be the pulmonary circulation, and low levels of ACE activity have been reported in chronic lung disease [10–1014]. The metabolism of serum ACE has not been clarified, but it is thought that the liver extracts the enzyme [15]. Cardiopulmonary bypass has been likened to the adult respiratory distress syndrome, and indeed the postoperative pulmonary complications of CPB can lead to the full-blown clinical picture of the adult respiratory distress syndrome. In adult respiratory distress syndrome ACE activity decreases [14]. Because CPB causes pulmonary endothelial dysfunction, we hypothesized that in children undergoing open heart operations the circulating thrombomodulin concentration would be increased while the serum ACE activity would be low. Because the pulmonary endothelium in children with pulmonary hypertensive congenital heart disease shows morphologic damage by 2 months of age [1], we hypothesized that the abnormalities would be greater in these children than in those with a normal or low pulmonary blood flow and arterial pressure.

	Patients and Methods

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Patients Studied
A total of 22 children were studied at cardiac catheterization, and 61 were studied before, during, and after intracardiac repair. All the children underwent elective repair, save 1 with obstructed total anomalous pulmonary venous return. All these studies were carried out during the course of routine monitoring procedures, and all were done with the permission of the Ethics Committee of the Hospitals for Sick Children, Great Ormond Street. The two studies, one on thrombomodulin and the other on serum ACE activity, were carried out on different children.

THROMBOMODULIN STUDIES.
Studies were carried out on three groups of subjects: The serum thrombomodulin level was determined at cardiac catheterization in 22 patients of similar age (Table 1). Thirteen had a normal or low pulmonary blood flow, with a median age of 11 months. Of these, 8 patients had tetralogy of Fallot and 2 had pulmonary stenosis, of whom 1 had transposed great arteries. Three other children had pulmonary atresia, 1 with an intact ventricular septum and 2 with a ventricular septal defect. Nine children with a median age of 10.5 months had an increase in flow. Of these, 5 had a ventricular septal defect, 2 had an atrioventricular septal defect, and 1 had a secundum atrial defect.

The serum thrombomodulin also was determined in 9 healthy adult volunteers.

STUDIES ON SERUM ANGIOTENSIN-CONVERTING ENZYME ACTIVITY.
Twenty-seven children with a median age of 2 years were studied (Table 3). Apart from their cardiac disease, all patients were well. None had parenchymal lung disease or liver or renal dysfunction. They were divided into three groups: Ten children (group I) had a secundum atrial septal defect (ASD) with a high pulmonary blood flow and were thought to have a normal pulmonary arterial pressure, as judged by clinical, radiographic and echocardiographic findings. Eight children (group II) had a posttricuspid left-to-right shunt and an increase in pulmonary blood flow, assessed by clinical examination with or without cardiac catheterization. They had either a ventricular septal defect (5), a complete atrioventricular septal defect (2), or transposition of the great arteries with a ventricular septal defect. The mean pulmonary arterial pressure was 29.8 mm Hg in the 5 patients catheterized. Nine children (group III) had a restricted pulmonary blood flow caused by tetralogy of Fallot (7) or transposition of the great arteries with pulmonary stenosis (2). Six of these patients underwent cardiac catheterization. Conventional anesthetic and CPB techniques were used. The mean duration of CPB and mean aortic cross-clamping time were both shorter in patients in group I with an ASD than in either of the other two groups (p < 0.05 for CPB and p < 0.01 for comparisons of aortic cross-clamping times). The peripheral venous serum level also was determined in 30 healthy young adult volunteers (group IV).

The serum thrombomodulin level was measured by an enzyme-linked immunoassay technique using a monoclonal antibody specific for thrombomodulin (TM Panacella, Fujirebio Co, Tokyo, Japan). The intraassay and interassay variations of these measurements were 5.5% and 5.8%, respectively. Serum ACE activity was measured using the methods described by Rohrbach [16] with a radiolabeled (glycine-1-¹⁴C) hippuryl-histidyl-leucine (Amersham International PLC, UK) as a substrate. Enzyme activity was measured as release of radiolabeled hippuric acid from the substrate, and expressed as units of activity per milliliter. The intraassay and interassay variations were 2.6% and 8.6%, respectively.

STATISTICAL ANALYSIS OF THROMBOMODULIN CONCENTRATION AND ACTIVITY.
All results were expressed as the mean ± standard error of the mean. The thrombomodulin and ACE levels in the patients studied during open heart operations were standardized to the pre-CPB concentration using the hematocrit value to overcome the effect of hemodilution: Corrected thrombomodulin or ACE level = measured level x (hematocrit before CPB/hematocrit when sample was taken). The thrombomodulin level and ACE activity before CPB was compared in those with a high and a low pulmonary blood flow using Student's t test for unpaired observations. In addition, the mean thrombomodulin level before CPB was compared in those with a high pulmonary blood flow in groups A and B. During and after operation, within each patient group the arterial and venous ACE activity at different time points was compared using Student's t test for paired observations. To assess the difference in the levels between the groups during and after CPB we calculated the sum total of thrombomodulin or ACE and the maximum value of each after the aortic cross-clamps were removed, for each group, and compared the groups by means of Student's t test (method of summary measures). Correlations were analyzed with the Spearman rank correlation coefficient. The findings were considered to be statistically significant when p was less than 0.05.

	Results

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Thrombomodulin Studies
PREOPERATIVE SERUM THROMBOMODULIN LEVEL AT CARDIAC CATHETERIZATION.
The mean serum thrombomodulin level in patients with a high pulmonary blood flow was 6.4 ± 0.7 ng/mL, higher than those with a low pulmonary blood flow, 2.9 ± 0.3 ng/mL (p < 0.01) (Fig 1). The serum thrombomodulin level in patients with a high pulmonary blood flow was also greater than in normal adult volunteers, 2.2 ± 0.1 ng/mL (p < 0.001).

View larger version (12K): [in this window] [in a new window]   Fig 1. . Mean (± standard error of the mean) serum thrombomodulin (TM) level in the patients who underwent cardiac catheterization, showing a higher TM level in those with a high pulmonary blood flow (Qp) than in those who had a normal or low flow (p < 0.01).

View larger version (17K): [in this window] [in a new window]   Fig 2. . Mean serum thrombomodulin (TM) levels in patients with a normal or low pulmonary blood flow (Qp) (closed circles), in the older patients with a high Qp (group A, open circles), and in the younger patients with a high Qp (group B, open triangles). (PRE = before cardiopulmonary bypass; OAC = aortic cross-clamps removed; OB = off bypass; times indicate subsequent sampling times; *p < 0.05, **p < 0.01 compared with the data before bypass [PRE] in each group.)

The mean preCPB thrombomodulin level in group B, the younger group of children with a high pulmonary blood flow, was similar to that seen in patients with a high flow in group A (see Fig 2). As in group A, the thrombomodulin level increased after operation, becoming significantly greater than the pre-CPB level at 3, 6, and 24 hours (p < 0.05 at all these times).

When all the preoperative thrombomodulin values in groups A and B were grouped together, there was no correlation between the thrombomodulin level and age.

STUDIES OF ANGIOTENSIN-CONVERTING ENZYME ACTIVITY.
The ACE activity was not significantly different between the arterial and venous samples in any group at any time point (Fig 3). Preoperatively, the mean arterial and venous determinations of ACE activity were similar in the three groups of patients, and all were similar to the mean value in the venous blood samples of the normal subjects. With the onset of CPB the serum ACE activity decreased significantly in all groups and then rose when CPB was discontinued. Throughout the sampling period before, during, and after CPB, the serum ACE activity in the three groups of children generally maintained the same ranking order: children with an ASD had a greater ACE level than those with reduced pulmonary blood flow, who had a greater level than those with high flow due to abnormalities other than an ASD and associated with moderate pulmonary hypertension (group I > III > II). Angiotensin-converting enzyme activity was significantly lower in patients in group II than in those in group I at the time the aortic cross-clamps were removed in both arterial and venous samples, and in the venous samples when CPB was discontinued (p < 0.05 for all comparisons). Also, the sum total of ACE activity during the whole study period in children with a high pulmonary blood flow in group II not caused by an ASD was significantly less than that in children with an ASD (p < 0.05 for both arterial and venous samples). Twenty minutes after the discontinuation of CPB serum ACE activity had returned to the pre-CPB level only in children operated on for a secundum ASD.

View larger version (26K): [in this window] [in a new window]   Fig 3. . Mean (± standard error of the mean) serum angiotensin-converting enzyme (ACE) activity expressed in units per milliliter for the (A) arterial and (B) venous samples. Closed circles indicate patients with an atrial septal defect (ASD), open circles indicate a high pulmonary blood flow (Qp), and open squares indicate a low flow. For abbreviations, see legend to Figure 2. (p < 0.05 between groups; *p < 0.05, **p < 0.01 compared with the prebypass ACE activity in each group.)

	Comment

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
In the present study the serum thrombomodulin level in children with an increase in pulmonary blood flow and pulmonary hypertension was greater than normal before the operation. The level in those with a reduced flow was normal. The ACE activity was normal preoperatively in all patients, irrespective of the hemodynamic abnormality. After CPB the thrombomodulin level was higher than normal in children who had had a high pulmonary blood flow preoperatively. The serum ACE activity was abnormally low in all patients, but the reduction was greater in those children who preoperatively had a high pulmonary blood flow associated with pulmonary hypertension. These findings confirm our original hypothesis and suggest that the pulmonary circulation is more vulnerable to the damaging effects of CPB in such patients.

We might have expected to find a progressive increase in thrombomodulin level and ACE activity with age, pulmonary blood flow, and arterial pressure because pulmonary vascular disease and pulmonary endothelial abnormalities increase in severity with age and with increase in pulmonary blood flow and pressure [1]. We did not do so, and this could have been due to the relatively small number of children available for study in each group. This is a regrettable but unavoidable limitation in this clinical study. However, the increase in thrombomodulin level preoperatively and the reduction in ACE activity occasioned by cardiopulmonary bypass in patients who survive and do well indicate that endothelial cell damage and dysfunction occurs early in the course of pulmonary vascular disease.

After intracardiac repair, although the thrombomodulin level increased in all patients, only in those who had a higher pulmonary blood flow preoperatively was the postoperative level increased significantly. Also, the sum total of serum thrombomodulin levels during the entire study period was significantly greater in those who had had a higher pulmonary blood flow than in those who had not. Thrombomodulin is released from the surface of endothelial cells only when the cells are morphologically damaged [5]. In vitro activation of endothelial cells by interleukin-1 or thrombin does not induce the release of thrombomodulin [5]. Earlier studies described thrombomodulin as a glycoprotein expressed on the surface of endothelial cells, which inactivates thrombin by binding to it, then inactivates protein C to cause thrombolysis [6]. It is extracted from the plasma by the liver and kidneys and has a half-life of 10 minutes [17–19]. The recognition of thrombomodulin as a selective and specific marker of acute endothelial injury is relatively recent [8]. Because the lung is normally thought to contain more thrombomodulin than any other organ, pulmonary endothelial damage may be particularly likely to cause an increase in the plasma levels [20]. Platelets are another possible source of thrombomodulin, but it has been calculated that the content of thrombomodulin in the endothelium of the entire body is 2.0 x 10⁴ that contained in all the circulating platelets [21].

Thus it appears that the preoperative serum thrombomodulin level is elevated in children whose lungs show morphologic endothelial damage associated with pulmonary hypertension and that the inflammatory response provoked by CPB is greater in such patients than in those with little or no preexisting damage. Pulmonary arterial endothelial cell abnormalities, such as an increase in cell thickness and in myofilament and microfilament tracts, are evident by 2 months of age in pulmonary hypertensive congenital heart disease, irrespective of the type of intracardiac abnormality [1]. Cell disruption and denudation occurred in slightly older children. Cardiopulmonary bypass is known to cause endothelial cell swelling, interstitial edema, and perivascular interstitial hemorrhage in adult patients undergoing coronary artery bypass grafting who do not have an increase in pulmonary blood flow [22].

The serum ACE activity was normal preoperatively in all patients, irrespective of pulmonary arterial pressure. These findings are similar to those of Salzer-Muhar and co-workers [23], although they did find a weak negative correlation between serum ACE activity and pulmonary arterial pressure and resistance. In our study too few children underwent cardiac catheterization to permit such analysis. While on CPB, ACE activity decreased in all patients, but the reduction in activity was greater in those who had a high pulmonary blood flow and pulmonary hypertension preoperatively. These patients still had an abnormally low ACE activity 20 minutes after CPB was discontinued, whereas in those with a high flow and normal pressure the activity had returned to normal. In experimental pulmonary hypertension induced in rats by the administration of monocrotaline, serum ACE remained normal but was reduced in the lung homogenates, the activity falling as pulmonary arterial pressure and right ventricular hypertrophy increased [24]. Our findings indicate that in pulmonary hypertensive children ACE activity is normal during daily life, as others had also found, but that the additional stress of CPB reveals evidence of endothelial dysfunction. Angiotensin-converting enzyme is an exopeptidase that converts the inactive decapeptide angiotensin-1 to the potent vasoconstrictor octapeptide angiotensin-2 but also inactivates the vasodilator nonapeptide bradykinin [25], and bradykinin has a marked direct vasodilator effect on the pulmonary circulation. A reduction in ACE activity may therefore help limit an increase in pulmonary arterial pressure as the pulmonary arteries undergo structural remodelling.

In the present study, the ACE activity in the cyanotic children decreased during and immediately after operation; the response was intermediate between those with a high pulmonary blood flow with and without pulmonary hypertension and not significantly different from either. No conclusion can be drawn from these observations although the failure to achieve a normal ACE activity level 20 minutes after CPB was discontinued may indicate preoperative and intraoperative endothelial damage in these patients. We did not find any correlation between the ACE activity and age, confirming work by other investigators [23, 26]. Also, simultaneous arterial and venous samples showed the same level of ACE activity, as might be expected if the enzyme is extracted outside the lung, in the liver [15].

In the patients with a high pulmonary blood flow the etiology of the abnormality in thrombomodulin and ACE activities, whether accentuated or revealed by CPB, is not known, but endothelial dysfunction is known to precede morphologic damage. All these patients probably had an increase in shear stress since birth.

The functional effects occasioned by the changes in serum thrombomodulin level and ACE activity during CPB must be speculative. Greater expression of thrombomodulin on the pulmonary endothelial cells surface might be expected to facilitate thrombolysis [6], but whether an increase in the circulating level of this glycoprotein might also have this effect is uncertain. A reduction in ACE activity will promote pulmonary vasodilatation by reducing the inactivation of bradykinin [27]. In conclusion, the findings in the present study emphasize the vulnerability of patients with preexisting pulmonary endothelial damage who undergo intracardiac repair. Studies such as these provide an opportunity to learn more about the metabolic function of the lungs.

	Acknowledgments

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
We are grateful to Miss Jayne Reader for carrying out the ACE assays on the control subjects. This work was supported by the Wellcome Trust.

	Footnotes

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Haworth, Vascular Biology and Pharmacology Unit, Institute of Child Health, 30 Guilford St, London, WC1N 1EH, England.

	References

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Sheila G. Haworth Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Komai, H. Articles by Haworth, S. G. Search for Related Content PubMed PubMed Citation Articles by Komai, H. Articles by Haworth, S. G.