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J Thorac Cardiovasc Surg 1994;108:960-968
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS,
MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

The dynamic change of plasma endothelin-1 during the perioperative period in patients with rheumatic valvular disease and secondary pulmonary hypertension

Zhi-Gang Zhu, MDa, Min-Sheng Wang, MDa, Zhen-Bin Jiang, MDa, Zhen Jiang, MDb, Shu-Xiang Xu, MDc, Chang-Yu Ren, MDa, Mei-Xin Shi, MDa


Shanghai, the People's Republic of China

Supported in part by the Chinese Medical Board.

Received for publication Nov. 17, 1993. Accepted for publication April 7, 1994. Address for reprints: Zhi-Gang Zhu, MD, Department of Cardiac Surgery, Zhong Shan Hospital, Shanghai Medical University, Shanghai 200032, the People's Republic of China.

Abstract

The arterial plasma endothelin-1 concentration was substantially more elevated in 15 patients with rheumatic valvular disease and secondary pulmonary hypertension than in healthy volunteers (3.66 ± 2.20 versus 1.17 ± 0.38 pg/ml, mean ± standard deviation; p < 0.01) The preoperative plasma endothelin-1 level was highly correlated with the pulmonary hemodynamics: pulmonary artery systolic pressure (r = 0.94, p < 0.001), pulmonary artery mean pressure (r = 0.86, p < 0.001), pulmonary capillary wedge pressure (r = 0.82, p < 0.001), and pulmonary vascular resistance (r = 0.63, p < 0.02). After valve replacement, the plasma endothelin-1 concentration declined substantially and the pulmonary hemodynamics improved markedly. Two weeks after the operation, the plasma endothelin-1 level in patients (1.26 ± 0.45 pg/ml, mean ± standard deviation) was not statistically different from that in the healthy volunteers. The plasma endothelin-1 concentration continuously increased during the course of cardiopulmonary bypass and peaked after cessation of bypass. The peak plasma endothelin-1 level (13.49 ± 4.60 pg/ml, mean ± standard deviation) positively correlated with the bypass time (r = 0.64, p < 0.02) and negatively correlated with the urine volume during bypass (r = -0.69, p < 0.01). We conclude that (1) increased plasma endothelin-1 might be implicated in the pathogenesis of secondary pulmonary hypertension caused by rheumatic valvular disease and (2) markedly elevated plasma endothelin-1 concentrations might be associated with the mechanism of cardiac or renal dysfunction after prolonged cardiopulmonary bypass. (J THORACCARDIOVASCSURG1994;108:960-8)

In 1988, Yanagisawa and colleaguesGo 1 isolated a 21-amino acid peptide, subsequently named endothelin (ET), from the supernatant of cultured porcine aortic endothelial cells. This substance is the most potent vasoconstrictor yet known and may play an important role in the regulation of vascular tone and blood flow distribution.Go Go 2-7 The ET family includes three distinct isopeptides: ET-1 (the human and porcine ET), ET-2, and ET-3. Endothelial cells produce ET-1 exclusively but the tissues producing ET-2 and ET-3 remain uncertain. Recent studies have shown that at least two different types of ET receptor existGo Go 8,9: the specific one is called ETA and the nonselective one is named ETB. Having high affinity for ET-1 and ET-2, ETA is located on the vascular smooth muscle cells and is responsible for constriction. ETB shows an equal affinity for all three types of ET, is situated on endothelial cells, and is responsible for production of endothelium-derived relaxing factor. After binding to its G-protein coupled receptor, ET activates phospholipase C, resulting in increased formation of inositol triphosphate and diacylglycerol, which promotes release of Ca2+ from intracellular stores and influx of Ca2+ through voltage-dependent Ca2+ channels. By such a mechanism, ET evokes its biologic actions. Besides the potent, sustained vasoconstrictive effect, ET exhibits a positive inotropic effect on myocardium, promitogenic effect, neuroendocrine effect, and various other pathophysiologic effects.Go Go 2-10 In the clinical setting, increasing evidence has showed that ET-1 might be involved in the pathogenesis of various diseases such as acute myocardial infarction, acute renal failure, and congestive heart failure.Go Go Go 3-5,7

Cardiopulmonary bypass (CPB) is a controlled pathologic process related to several mechanisms such as nonpulsatile perfusion, hypothermia, and hemodilution. In clinical practice, the morbidity of cardiac or renal dysfunction has been observed to increase markedly after prolonged CPB.

The aims of the present study were as follows: (1) to investigate the change of plasma ET-1 in patients with rheumatic valvular disease who have secondary pulmonary hypertension and its response to valve replacement and (2) to clarify the dynamic change of plasma ET-1 during the course of CPB.

PATIENTS AND METHODS

Fifteen patients with rheumatic heart disease underwent valve replacement. Seven had a simple mitral valve lesion and eight had combined mitral and aortic lesions.

The patients' mean age was 41 ± 9 years (mean ± SD*). There were eight male and seven female patients. According to the New York Heart Association (NYHA) classification, two patients were in class I, six in class II, four in class III, and three in class IV. Except two patients with normal cardiac function, the remaining patients received regular doses of oral diuretics and digitalis up to the night before the operation. The routine biochemistry examinations of liver and renal function revealed no abnormalities in any patients before the operation. The study protocol was approved by the Human Research Committee at Zhong Shan Hospital of Shanghai Medical University and informed verbal consent was obtained from each patient.

Premedication was given by meperidine (1 mg/kg body weight), droperidol (0.1 mg/kg body weight), and scopolamine hydrobromide (0.06 mg/kg body weight) injected intramuscularly 30 minutes before the operation. A radial artery catheter was placed percutaneously for continuous monitoring of systemic arterial pressure. A flow-directed, triple-lumen 7F Swan-Ganz catheter (Gould, model SP 5107, Gould Inc., Oxnard, Calif.) was inserted through the right internal jugular vein and advanced into the pulmonary artery under the guidance of a pressure curve. Induction and maintenance of anesthesia were achieved with fentanyl (30 to 35 µg/kg body weight), droperidol (200 µg/kg body weight), and pancuronium bromide (130 to 200 µg/kg body weight). Controlled mechanical ventilation (inspired oxygen fraction 1.0, tidal volume 8 to 10 ml/kg body weight, and frequency 12 to 14 breaths/min) was performed during the operation. Heart rate was recorded from precordial electrocardiographic leads. Simultaneous recordings were obtained of radial artery pressures and pulmonary artery pressures as systolic, diastolic, and mean. Central venous pressure, right atrial pressure, and pulmonary capillary wedge pressure were measured and recorded intermittently.

The operation was performed through a median sternotomy. The superior and inferior venae cavae and ascending aorta were cannulated separately to institute the bypass circuit. Heparin (3 mg/kg body weight) was administered to maintain an activated clotting time of more than 400 seconds during CPB. Moderate hypothermia (26° ± 1° C of the lowest nasopharyngeal temperature, mean ± SD) and moderate hemodilution (30 ml/kg body weight of composite Ringer's lactate solution given as the prime fluid) were performed. A membrane oxygenator (Maxima; Medtronic Inc., Minneapolis, Minn.) was used to maintain satisfactory oxygenation during bypass. Nonpulsatile perfusion was achieved by using a roller pump (Sarns 7400; Sarns Inc./3M, Ann Arbor, Mich.) at a flow rate of more than 2.4 L/m2 · min. Cold potassium cardioplegic solution (K+:18 mmEq/L) was infused into the aortic root for cardiac arrest. Topical cooling of the heart was by iced slush. Protamine sulfate was administered in a ratio of 1.5:1 to the initial heparin dose to neutralize the heparin effect after CPB was ended. In all, 15 mitral and eight aortic prosthetic mechanical valves (Medtronic Hall, model 7700; Medtronic Inc., Minneapolis, Minn.) were implanted. The aortic crossclamp time was 59 ± 18 minutes (mean ± SD) and the bypass time was 100 ± 39 minutes (mean ± SD). The lowest nasopharyngeal temperature during CPB was 26° ± 1° C (mean ± SD), the mean perfusion pressure was 59 ± 8 mm Hg (mean ± SD), and the urine volume during CPB was 465 ± 210 ml (mean ± SD). All patients were given ventilatory support on the operative day and then extubated the following morning. All patients recovered uneventfully and were discharged from the hospital within 2 weeks after the operation.

Hemodynamic monitoring
Cardiac output was measured in triplicate by the thermodilution method with a cardiac output computer (Gould SP 1435; Gould Inc.) at the following times: (1) before induction of anesthesia; (2) before CPB, after cannulation; (3) after cessation of CPB; (4) at the end of the operation; (5) 12 hours after the operation; and (6) 24 hours after the operation.

Other hemodynamic parameters were calculated by standard formulas as follows:


where CI = cardiac index, CO = cardiac output, BSA = body surface area, SVI = stroke volume index, HR = heart rate, SVR = systemic vascular resistance, SAP = systemic artery pressure; RAP = right atrial pressure, PVR = pulmonary vascular resistance, PAP = pulmonary artery pressure, and PCWP = pulmonary capillary wedge pressure.

Sample collection and processing
A 4 ml sample of radial artery blood was drawn from each patient for the measurement of ET-1 at the following times: (1) before induction of anesthesia; (2) before CPB, after cannulation; (3) 10 minutes after the nasopharyngeal temperature had dropped to 28° C, with bypass started and the aorta crossclamped; (4) after removal of the aortic crossclamp, still on bypass; (5) after cessation of bypass; (6) at the end of the operation; (7) 12 hours after the operation (8) 24 hours after the operation; and (9) 2 weeks after the operation.

Among five patients, 4 ml of pulmonary artery blood for the measurement of ET-1 in mixed venous blood was drawn through the Swan-Ganz catheter simultaneously at the following times: 1, 2, 5, 6, 7, and 8.

In 10 healthy volunteers, 4 ml of radial artery blood was taken to determine the ET-1 concentration in normal subjects.

The blood sample was collected with a chilled syringe and transferred into a polypropylene tube containing aprotinin (500 KIU/ml) and ethylenediaminetetraacetate (1 mg/ml) at 4° C. The sample was kept on ice and centrifuged at 3000 g for 15 minutes at 0° C. All separated plasma samples were then immediately stored at -80° C until analysis.

ET-1 assay
Plasma ET-1 concentration was determined by a modification of the radioimmunoassay previously described.Go 11

After thawing, 2 ml plasma was acidified with an equal amount of 0.1% trifluoroacetic acid (TFA) and centrifuged at 6000 g for 20 minutes at 4° C to remove proteolytic activity. The supernatant was applied to a Sep-Column cartridge containing 200 mg of C18 (Peninsula Lab. Inc., Belmont, Calif.) that had been preactivated by successive washing of 60% acetonitrile in 0.1% TFA (1 ml, once) followed by 0.1% TFA (3 ml, three times). After the cartridge was washed with 0.1% TFA (3 ml, twice), the immunoreactive ET-1 was slowly eluted with 60% acetonitrile in 0.1% TFA (3 ml, once) into a polypropylene tube. The extracts were lyophilized in a freeze dryer (Snijders Scientific B.V., Tilburg, The Netherlands) and then stored at 4° C. The recovery rate of ET-1 during extraction was 83% ± 2% (mean ± SD) as assessed by calculating the recovery of known quantities of standard ET-1 added to plasma.

Samples and standards (ET-1; Peninsula Lab. Inc.) were reconstituted in assay buffer and incubated for 24 hours at 4° C with rabbit anti-ET-1 serum (Peninsula Lab. Inc.). About 13,000 cpm of 125I-labeled ET-1 was added to each tube and a second 24-hour incubation at 4° C followed. On the third day, goat antirabbit immunoglobulin G serum and normal rabbit serum were added and incubated at room temperature for 2 hours. After centrifugation at 1700 g for 20 minutes, the supernatant was discarded by aspiration and the precipitate was counted for 125I radioactivity. The standard curve was then constructed by calculating the percentage of B/Bo after logit/log transformation (where B = bound radioactivity in the presence of standard or sample and Bo = bound radioactivity in the absence of ET-1). The ET-1 concentration of the sample was determined from the standard curve and presented after correction for the recovery rate.

The antibody used in this study exhibited a cross-reactivity of 100% with human ET-1, 7% with human ET-2, 7% with human ET-3, and 17% with human big ET, respectively. The antibody did not cross react with human {alpha}-atrial natriuretic polypeptide, human angiotensin I, II and III, [Arg Go 8]-vasopressin, human corticotropin, and human vasoactive intestinal peptide. Owing to the low cross-reactivity, the results given in this study should be considered as immunoreactive ET-1. The lower limit of detection was 0.25 pg/tube. The intraassay and interassay coefficients of variation were 7% and 9%.

All ET-1 values were expressed as picograms per milliliter. The effect of hemodilution during CPB on plasma ET-1 concentration was corrected by the formula: BPC = BP(BLHct/[BPHct - BLHct]/[1 - BLHct]) where BPC = dilution-corrected protein (ET-1) concentration during CPB, BP = measured protein (ET-1) concentration during CPB, BL = baseline (pre-bypass value), and Hct = hematocrit.

Statistical analysis
Difference of plasma ET-1 concentration between patients and healthy volunteers was determined by Student's t test (unpaired). To assess the relation of plasma ET-1 level to NYHA classification class, we used the H test (Kruskal-Wallis test). Comparison of the plasma ET-1 concentrations between different points in time was by analysis of variance. Comparison of plasma ET-1 concentration between arterial blood and mixed venous blood was by Student's t test (paired). To identify relevant relations, we performed a linear regression analysis of hemodynamic and other parameters with plasma ET-1 level. All group values are expressed as mean ± SD. Significance was accepted at a p value less than 0.05.

RESULTS

Plasma endothelin-1
The arterial plasma ET-1 concentrations of healthy volunteers and patients were 1.17 ± 0.38 pg/ml and 3.66 ± 2.20 pg/ml, respectively. The difference between the two groups was significant (p < 0.01). No correlation was found between plasma ET-1 concentration and age or sex in patients or in the healthy volunteers. ET-1 level did not correlate with NYHA class in patients.

Hemodynamic monitoring
The results of perioperative hemodynamic measurement are presented in GoTable I. Preoperatively, elevated pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance clearly demonstrated pulmonary hypertension resulting from the rheumatic valvular lesion. After the operation, the pulmonary hemodynamics greatly improved as pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance decreased substantially.


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  		Table I. Hemodynamic measurements during perioperative period (n = 15)
 
The preoperative plasma ET-1 level had shown positive correlations with pulmonary artery pressure (systolic, diastolic, and mean), pulmonary capillary wedge pressure, pulmonary vascular resistance, and systemic vascular resistance but negatively correlated with cardiac output, cardiac index, and stroke volume index. No relations were found between preoperative ET-1 level and heart rate, systemic arterial pressure (systolic, diastolic, and mean), central venous pressure, or right atrial pressure (GoTable II).


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  		Table II. Linear regression data (n = 15): Plasma endothelin-1 versus hemodynamic parameters before operation
 
The change of plasma ET-1 concentration during the perioperative period
The arterial plasma ET-1 concentration rose after the start of the operation. After cannulation but before bypass, the ET-1 concentration was 4.15 ± 2.40 pg/ml, which was not statistically different from the baseline level. After CPB was started, the aorta crossclamped, and 10 minutes after the nasopharyngeal temperature had decreased to 28° C, the ET-1 level increased dramatically to 10.14 ± 4.38 pg/ml, significantly different from the baseline level (p < 0.01), but showed no correlation with the lowest nasopharyngeal temperature (r = 0.20, p > 0.05). After removal of the aortic crossclamp, ET-1 concentration continuously increased to 10.99 ± 4.95 pg/ml but did not correlate with the aortic crossclamp time (r = -0.29, p > 0.05). When CPB ended, plasma ET-1 concentration reached its peak value of 13.49 ± 4.60 pg/ml and positively correlated with the time of CPB duration but negatively correlated with the urine volume during CPB. No association of the peak ET-1 level with aortic crossclamp time or mean perfusion pressure was found (GoTable III). At this time, the plasma ET-1 level was significantly different from the baseline level (p < 0.01). At the end of the operation, the plasma ET-1 concentration declined to 6.89 ± 3.00 pg/ml, which was significantly different from the level at cessation of CPB (p < 0.01) but still remained higher than the baseline concentration (p < 0.01). Twelve hours after the operation, the plasma ET-1 concentration was 4.29 ± 1.89 pg/ml. The ET-1 level continuously declined to 2.88 ± 1.45 pg/ml 24 hours after the operation, a value not statistically different from the baseline level (p > 0.05). Two weeks after the operation, the plasma ET-1 concentration fell to 1.26 ± 0.45 pg/ml, significantly lower than the preoperative level (p < 0.01), and was not statistically different from the level in the healthy volunteers. The dynamic change in plasma ET-1 concentration during the perioperative period is illustrated in Fig. 1.


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  		Table III. Linear regression data (n = 15): Plasma endothelin-1 versus operative parameters after cessation of CPB
 


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  		Fig. 1. The dynamic change of arterial plasma ET-1 concentration at different times during perioperative period (n = 15): A, before induction; B, after cannulation, before CPB; C, 10 minutes after temperature decreased to 28° C (on bypass and aorta clamped); D, after removal of aortic crossclamp; E, after cessation of bypass; F, at end of operation; G, 12 hours after operation; H, 24 hours after operation; I, 2 weeks after operation. All values are expressed as mean ± SD. *p < 0.01 versus A.

 
Plasma ET-1 concentration in arterial blood and mixed venous blood
In five patients studied, the dynamic change of plasma ET-1 concentration in mixed venous blood was similar to that in arterial blood. The venous ET-1 level was a little lower than the arterial level before induction (2.75 ± 1.04 versus 3.25 ± 1.23 pg/ml), before bypass (3.25 ± 0.94 versus 3.64 ± 1.95 pg/ml), and after cessation of CPB 11.51 ± 2.45 versus 12.13 ± 3.30 pg/ml), but the differences did not reach statistical significance. At the end of the operation (7.76 ± 2.31 versus 6.74 ± 2.53 pg/ml) and 12 hours after the operation (5.69 ± 1.74 versus 3.89 ± 1.58 pg/ml), ET-1 concentration in mixed venous blood became higher than in arterial blood, but still no significant differences were found. Twenty-four hours after the operation, the venous ET-1 level reached 4.03 ± 0.91 pg/ml, higher than the arterial level (2.44 ± 0.50 pg/ml); a statistically significant difference (p < 0.01) was observed (Fig. 2).



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  		Fig. 2. Comparison of plasma ET-1 concentration between pulmonary artery and radial artery at different times during perioperative period (n = 5). Values are mean ± SD. *p > 0.05 versus radial artery level. p < 0.01 versus radial artery level.

 
DISCUSSION

In this study, the plasma ET-1 concentration was significantly elevated in patients with rheumatic valvular disease who had secondary pulmonary hypertension and was about twofold greater than that in normal subjects. Similar results were also obtained by other authors.Go Go 12-14 Positive correlations between preoperative plasma ET-1 level and pulmonary hemodynamic variables such as pulmonary artery pressure (systolic, diastolic and mean), pulmonary capillary wedge pressure, and pulmonary vascular resistance were also found, which strongly implied that ET-1 might be involved in the pathologic process of secondary pulmonary hypertension.

Lung is the major organ responsible for ET-1 clearance inasmuch as up to two thirds of 125I-labeled ET-1 disappeared in a single passage through the pulmonary circulation.Go Go 15,16 Not only pulmonary vascular endothelial cells but also pulmonary endocrine cells could secrete ET-1.Go 17 The structural alterations in secondary pulmonary hypertension are diffused intimal fibrosis and medial hypertrophy in the small pulmonary arteries, arterioles, and venules. It could be speculated that under the condition of secondary pulmonary hypertension, abnormal pulmonary vascular endothelial cells, as well as pulmonary endocrine cells, might produce excessive ET-1; meanwhile the hypertrophied vascular smooth muscle cells might have decreased ability to process ET-1. As the result of increased production and decreased degradation in the lung, plasma ET-1 concentration rose. ET-1 exhibits mitogenesis action. Komuro and associatesGo 18 found that ET-1 stimulated the expression of c-fos and c-myc genes which were associated with proliferation of vascular smooth muscle cells. Supposed to be an autacoid, ET-1 secreted by endothelium cells might act locally to be a potent stimulant for hypertrophy of the intima and underlying media of pulmonary vasculature. Pulmonary arteries and veins are sensitive to the constrictor effect of ET-1, and pulmonary arteries are much more severely affectedGo Go 19,20; thus the increased plasma ET-1 level might further contribute to the deterioration of secondary pulmonary hypertension.

From our study, we observed that after valve replacement the pulmonary hemodynamics markedly improved as pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance decreased significantly. In the meantime, the plasma ET-1 level also declined rapidly. The plasma ET-1 level was significantly lower in arterial blood than in mixed venous blood 24 hours after the operation, a finding similar to that in healthy subjects.Go 12 Two weeks after the operation, all patients underwent echocardiography by the Doppler technique. The mean pulmonary artery systolic pressure was within the normal limit (<30 mm Hg) as assessed by the velocity of tricuspid regurgitation flow. At that time, the patients' plasma ET-1 level was significantly lower than the preoperative level but showed no statistical difference from that of normal subjects. We suppose that (1) the plasma ET-1 concentration could be an indicator of the severity of secondary pulmonary hypertension caused by rheumatic valvular disease and (2) ET-1 might implicate and accelerate the pathogenesis of secondary pulmonary hypertension. However, ET-1 might be only a mediator, but not a pathogenic factor.

As yet, a limited number of studies have addressed the change of plasma ET-1 during CPB.Go Go 21-23 Hynynen and associatesGo 21 first reported that plasma ET-1 concentration increased significantly during bypass and remained elevated until the end of the operation. They speculated that this increase might be caused by hypothermia during CPB. Their report was only a preliminary observation; detailed information was not presented. Knothe and colleaguesGo 22 found that the plasma ET-1 level continuously increased during the whole bypass period, dropped at the end of the operation, and then increased again to the peak value 4 hours after the operation in the intensive care unit. In their study, the bypass was "partial" during the whole period and was close to normothermia (rectal temperature 34° ± 0.5° C). The ET-1 concentration was not corrected for the effect of hemodilution. What we used in this study is so-called "conventional bypass," which included moderate hemodilution, moderate hypothermia, and nonpulsatile perfusion. The subjects studied were limited to the patients with rheumatic valvular disease, and the ET-1 concentration was presented after correction for the recovery rate during extraction and for the hemodilution effect during CPB, so that the result is comparable. In our study, the plasma ET-1 level continuously increased during the course of CPB.

Besides those conditions such as surgical manipulation and stress that might contribute to the increase in plasma ET-1,Go Go 24,25 there are five other possible mechanisms:

  1. One such mechanism is hypotension. Cernacek and StewartGo 11 found that plasma ET-1 concentration rose markedly in patients with cardiogenic shock, which might exert a beneficial effect by augmenting vascular resistance to maintain systemic perfusion pressure in the face of life-threatening hypotension.
  2. A second possible mechanism is nonpulsatile perfusion. The altered flow pattern, quite different from that in the normal physiologic state, might cause shear damage to vascular endothelial cells to stimulate ET-1 secretion.Go 26
  3. A third mechanism is platelet aggregation and dysfunction, a well-known phenomenon during CPB owing to the contact with nonphysiologic surfaces.Go 27 Thromboxane A2, a product of activated platelets, was increased during bypass.Go 28 In vitro study has shown that platelets could directly stimulate the production of ET-1 in cultured endothelial cells,Go 29 and the thromboxane A2 analog had a similar effect.Go 30
  4. The sequestration of lung during CPB makes ET-1 lose its major processing factory in the human body. Under the conditions of hypotension and hypothermia, the human metabolic rate decreases so that organs such as liver and kidney might lower the extraction rate of ET from the circulating blood.
  5. Coronary artery endothelial cell dysfunction caused by global myocardial ischemia and reperfusion injury might also be responsible for the continuous increase of plasma ET-1 after removal of the aortic crossclamp.

In a study by Pearson, Lin, and Schaff,Go 31 the production of endothelium-derived contracting factor was enhanced after coronary reperfusion. The ET-1 binding site density of rat cardiac membrane was markedly increased by global ischemia and was further enhanced by reperfusion, as reported by Liu and colleagues.Go 32 Moderate blood cooling during general anesthesia would not stimulate the release of ET-1, which is in contrast to the raised plasma ET-1 level following cold pressor test in the conscious state,Go 33 because the plasma ET-1 concentration measured 10 minutes after the temperature had reached 28° C did not correlate with the lowest nasopharyngeal temperature. In the present study, the peak level of plasma ET-1 occurred after cessation of CPB and positively correlated with the bypass duration time, which strongly implied that the loss of the lung's clearing function might play a major role in the increase of circulating ET-1 during CPB.

The maximal ET-1 concentration in this study showed a negative correlation with the urine volume during CPB, suggesting that the increased ET-1 might have an effect on renal function. In vivo and in vitro studies have shown that renal vasculature is particularly sensitive to the constrictor effect of ET-1 in comparison with coronary arteries or intestinal mesenteric arteries. Intravenous bonus injection or infusion of ET-1 at pathophysiologic concentration resulted in a dose-dependent, sustained decrease of renal blood flow and glomerular filtration rate.Go Go 34,35 In clinical practice, the plasma ET-1 level was profoundly elevated in patients with acute renal failure but fell after renal function improved.Go Go 36,37

The fact that peak plasma ET-1 concentration occurred at the end of CPB may have clinical importance. Although the peak value of ET-1 shown in this study was far below the ET-1 concentration needed to induce coronary artery spasm in vitro, what will the plasma ET-1 level be if CPB lasts for more than 3 hours? Inasmuch as there is a wide distribution of ET-1 receptors within the coronary vasculature and coronary resistive vessels had proved to be more sensitive to the vasoconstricting effect of ET than the conductive vessels,Go Go 38,39 would ET-1 be a promising candidate accounting for coronary spasm early after cardiac surgery? Go Go 40-42 It is speculated that circulating ET-1 may be merely the "spillover" or "overflow" by endothelial cells and the ET-1 concentration in situ might be much higher than its blood level. Yang and colleaguesGo 43 reported that a low concentration of ET-1 could potentiate the constrictive effect of other vasoactive substances, such as norepinephrine and serotonin, on human internal mammary arteries. This observation implies that although the low plasma ET-1 was not sufficient to induce vascular spasm alone, the amplifying characteristic of ET-1 might predispose to the induction of spasm. Toyo-oka, Aizawa, and SuzukiGo 44 found that the peripheral venous and coronary sinus plasma ET-1 concentrations in patients with vasospastic angina were 1.71-fold and 2.11-fold, respectively, higher than in the patients without vasospastic angina.Go 44 They proposed that the increased ET-1 might be involved in the mechanism of coronary spasm. It has also been found that veins typically contract at a lower dose of ET than that required to contract arteries.Go 45 The question then is whether the elevated plasma ET-1 level will have a preferential effect on the grafted saphenous veins after coronary bypass operations.Go 46 Further studies are warranted.

The higher level of plasma ET-1 at the end of the operation in this study might be caused by the increasing secretion of thrombin and transforming growth factor-ß from the damaged tissues during the early phase of repair. These two substances were found to enhance the release of ET-1 from cultured endothelial cells.Go Go 30,47 In a recent study by Onizuka and coworkers,Go 48 there was a significant correlation in plasma level between ET-1 and thrombin-antithrombin III complex immediately after open chest operations.

In conclusion, we found that plasma ET-1 concentration rose markedly in patients with rheumatic valvular disease as a result of pulmonary hypertension and was positively correlated with the pulmonary hemodynamics, which suggests that ET-1 may be implicated in the pathogenesis of secondary pulmonary hypertension. We also found that the plasma ET-1 level significantly increased during CPB and peaked at the end of CPB. Elevated ET-1 is supposed to be associated with cardiac or renal dysfunction after prolonged CPB.

Footnotes

From Departments of Cardiac Surgery a andAnesthesiology, b Zhong Shan Hospital, Shanghai Medical University, and Nan Yang Medical RIA Center, c Shanghai, the People's Republic of China. Back

*SD = Standard deviation. Back

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