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Eur J Cardiothorac Surg 2002;21:218-223
© 2002 Elsevier Science NL

Plasma levels and vascular effects of endothelin and big endothelin in patients with stable and unstable angina pectoris undergoing coronary bypass grafting

Ulf Lockowandt*, Staffan Bjessmo, Torbjörn Ivert, Anders Franco-Cereceda

Department of Thoracic Surgery, Karolinska Hospital, 171 76 Stockholm, Sweden

Received 16 July 2001; received in revised form 1 October 2001; accepted 21 November 2001.

* Corresponding author. Tel.: +46-8-5177-0000; fax: +46-8-32-2701
e-mail: ulf.lockowandt{at}ks.se


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objectives: The aim of this study was to determine the plasma and pericardial levels of endothelin-1 (ET-1) and its precursor big endothelin-1 (Big ET-1) in patients with unstable and stable angina prior to and following coronary bypass surgery. To further investigate the content of ET-1, tissue levels were studied in the internal mammary artery (IMA) in patients with stable and unstable angina pectoris. Finally, the difference in reactivity of the IMA to ET-1 and Big ET-1 in stable and unstable patients was evaluated. Methods: Plasma and pericardial levels of ET-1 and Big ET-1 were determined with radioimmunoassay in 81 patients (33 unstable) immediately before coronary bypass surgery, and at 6, 14, 40 and 64 h following the procedure. Specimens of the distal IMA from 12 patients (six unstable) were collected at the beginning of surgery for determination of tissue levels of ET-1. Additionally, distal internal mammary arteries were obtained from another 24 patients (12 unstable). These vessels were mounted in organ baths for functional studies on vascular reactivity to ET-1 and Big ET-1. Results: The peripheral plasma levels of ET-1 in unstable patients were significantly lower in patients with unstable angina compared with patients with stable angina pectoris at all points of measurement. The levels of Big ET-1 were significantly higher pre-operatively in the unstable group, but decreased to similar levels to those of stable patients following coronary bypass grafting. There was no difference in ET-1 tissue content in the IMA between the patients. ET-1 and Big ET-1 caused an endothelinA (ETA)-receptor blocker sensitive, concentration-dependent contraction of the IMA obtained from stable as well as unstable patients. Conclusions: It is concluded that unstable angina pectoris is associated with an increased ET-1 turnover. This increased turnover may participate in the local regulation of coronary vascular tone with subsequent influence of the condition of the patients. The present investigation also implies that ETA-blockade may be useful as an additional pharmacological principal in the treatment of unstable angina pectoris prior to revascularization, as well as to prevent post-operative arterial graft spasm.

Key Words: Unstable angina pectoris • Coronary artery bypass grafting • Endothelin • Internal mammary artery


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
The pathophysiology behind unstable angina pectoris is complex. The rupture of a vulnerable atherosclerotic plaque is crucial. It exposes inflammatory cells such as macrophages and polymorphonuclear leukocytes and also causes a thrombus formation. The aggregated platelets in turn release vasoactive substances leading to vasoconstriction and increased coronary reactivity to vasoconstrictor stimuli [1,2].

Endothelin (ET) is the most potent endogenous vasoconstrictor yet discovered [3]. ET is a 21-amino acid peptide, generated from the 38-amino acid precursor big endothelin (Big ET) through ET converting enzymes. Among three isoforms (ET-1, -2 and -3), ET-1 is the major form not only produced by endothelial cells but also found in macrophages and polymorphonuclear leukocytes [4,5]. ET has been shown to evoke a variety of effects in the cardiovascular system including systemic and coronary vasoconstriction, pulmonary vasodilatation and positive inotropic and chronotropic actions, as well as negative inotropic effects [6–9]. Numerous pathophysiological disorders, including acute myocardial infarction, atherosclerosis and end-stage heart-failure, are associated with increased circulating plasma levels of ET [10,11]. However, results concerning plasma levels of ET in patients with stable and unstable angina are conflicting. Several studies have shown an increased level of Big ET-1 in unstable patients [12,13], while ET-1 levels have been shown to be both increased and decreased in unstable patients [14–18]. There are, to our knowledge, no studies evaluating the influence of coronary bypass grafting (CABG) on Big ET-1 and ET-1 levels in these patients.

The aim of this study was therefore to determine the plasma levels of ET-1 and its precursor Big ET-1 in unstable and stable patients prior to CABG, and to find out to what extent these levels were influenced by a surgical revascularization. Peri-operative ET-1 levels in the pericardial fluid were also measured. In addition, possible differences in graft tissue ET-1 concentration and vascular reactivity to ET-1 and Big ET-1 were studied in stable and unstable angina pectoris patients.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
This study was approved by the Ethics Committee of the Karolinska Hospital.

2.1. Determination of ET-1 and Big ET-1 levels in plasma, pericardial fluid and internal mammary artery tissue
The plasma and pericardial levels of ET-1 and Big ET-1 were determined in 81 patients subjected to routine CABG using cardiopulmonary bypass with ante- and retrograde blood cardioplegia. Thirty-three patients were unstable, all in Braunwald class IIIB, i.e. angina at rest within 48 h preceding the operation [19]. The patients’ characteristics are listed in Table 1.


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  		Table 1. Patient characteristicsa

 
Plasma for analysis of ET-1 and Big ET-1 was obtained from a peripheral vein immediately before the operation and at 6, 14, 40 and 64 h following the procedure. Pericardial fluid was obtained immediately on opening of the pericardium. The samples were collected in vacuum tubes, kept in ice slush, and centrifuged (10 min, 4 °C) at 1620xg. The plasma was then frozen at -70 °C and stored until analysis.

Distal internal mammary artery (IMA) segments for tissue determination of ET-1 were obtained from 12 patients (six unstable) at the beginning of the operation. The patients’ characteristics are listed in Table 1. Peripheral plasma samples for a comparative ET-1 determination were obtained simultaneously with the harvesting of the IMA segments. The plasma samples were treated as described above.

After extraction of tissue samples and plasma, the content of ET-1-like immunoreactivity was then determined by radioimmunoassay using an antiserum raised against ET-1 in rabbits (6901, Peninsula, Belmont, CA). Similarly, Big ET-1 was determined with a commercially available antiserum (6912, Peninsula, Belmont, CA). Human ET-1 or Big-ET-1 labelled with iodine-125 was used as tracer, and synthetic ET-1 or synthetic Big ET-1 (Neosystem, Strasbourg, France) as standard. The assay samples were incubated at 4 °C in 0.1 mol/l phosphate buffer, pH 7.4, containing 0.1% bovine serum albumin and 0.1% Triton-X. The detection limit of the ET assay was 1.0 pmol/l and for the Big ET-1 assay 1.0 pmol/l [20].

2.2. Functional experiments
Distal IMAs were obtained from a total of 24 patients (12 patients with unstable angina) undergoing CABG. All vessels (1–2 mm in length) were mounted in 2 ml organ baths on two L-shaped holders (diameter, 0.3 mm). A resting tension of 10 mN was then applied by adjusting one of the metal holders. The other holder was connected to a Grass polygraph model 7B (Grass Instrument Co., West Warwick, RI) for recording of isometric tension. The resting tension was chosen on the basis of preliminary experiments in which reproducible contractions were obtained at this resting tension. The vessels were kept in Tyrode's solution (pH 7.4) of the following composition: 137 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl2, 1.05 mM MgCl2, 11.9 mM NaHCO3, 0.42 mM NaH2PO4, and 5.6 mM glucose. The Tyrode's solution was aerated with 95% oxygen and 5% carbon dioxide at 37 °C. After 60 min of equilibration, during which the resting tension was adjusted to compensate for the spontaneous decline in arterial tension, circular contractions were induced by Tyrode's solution in which the NaCl had been replaced with equimolar amounts of KCl to give a final K+ concentration of 127 mM. Only vessels responding with two reproducible contractions to K+ exposure were used. Each experimental procedure was performed in vessels from at least six different patients. ET-1 and Big ET-1 were added to the organ baths in a cumulative fashion. The functional effects of these agents were studied under control conditions and after ETA-receptor blockade using BQ-123.

2.3. Drugs
Big ET-1 and ET-1 were obtained from Peninsula, Belmont, CA. BQ-123, a synthetic and highly selective ETA-receptor antagonist, was obtained from Clinalfa, Läufelfingen, Switzerland.

2.4. Statistical evaluation
Values are given as means±standard error of the mean (SEM). For the functional experiments, values are expressed as the percentage of contractions induced by a 127 mM concentration of K+ in control experiments. For statistical evaluation, the Mann–Whitney U-test was used; P<0.05 was considered significant (GraphPad Software. Instat 2.01).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. ET-1 and Big ET-1 levels in plasma, pericardial fluid and IMA tissue
The peripheral plasma levels of ET-1 in the unstable group were 4.6±0.4, 6.7±0.4, 5.6±0.4, 5.6±0.4 and 5.5±0.5 fmol/ml, immediately pre-operatively and at 6, 14, 40 and 64 h post-operatively, respectively. The corresponding ET-1 levels in the stable group were 6.1±0.3, 8.0±0.4, 7.7±0.4, 7.1±0.4 and 6.6±0.4 fmol/ml. There was a significant difference between the unstable and stable group at all points of measurement (Fig. 1) .



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  		Fig. 1. Peripheral levels of ET-1, pre-operatively and at 6, 14, 40 and 64 h post operatively in unstable (open squares) and stable (black squares) patients. Values are given as means±SEM. *P<0.05; **P<0.01; ***P<0.001, Mann–Whitney U-test. P, pre-operatively.

 
The plasma levels in the unstable group of Big ET-1, sampled according to the same protocol as ET-1, were 40±5, 39±3, 33±3, 29±3 and 31±3 fmol/ml. The matching Big ET-1 levels in the stable group were 28±3, 34±4, 32±3, 28±3 and 29±3 fmol/ml, with a significant difference in the pre-operative levels only (Fig. 2) . The differences in plasma levels of ET-1 and Big ET-1 levels were not related to the presence of hypertension, hyperlipidaemia or diabetes mellitus or related to any differences in medication (data not shown).



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  		Fig. 2. Peripheral levels of Big ET-1, pre-operatively and at 6, 14, 40 and 64 h post-operatively in unstable (open squares) and stable (black squares) patients. Values are given as means±SEM. *P<0.05, Mann–Whitney U-test. P, pre-operatively.

 
The pericardial levels of ET-1 were 8.2±0.7 fmol/ml in the unstable group and 10.3±0.8 fmol/ml in the stable group (P<0.05), while the corresponding levels of Big ET-1 were 39.3±3 and 43.0±4 fmol/ml in the unstable and stable group, respectively (P>0.05).

The content of ET-1 levels in IMA tissue in the unstable group was 0.6±0.2 pmol/g, and in the peripheral plasma from the same patients, 6.4±0.4 fmol/ml. ET-1 content in IMA tissue in the stable group was 0.5±0.2 pmol/g, and in the peripheral plasma from the same patients, 7.3±0.1 fmol/ml. There were no significant differences between the groups.

3.2. Functional experiments
Potassium (127 mM) exposure evoked a contraction of 1.03±1.1 and 0.8±0.9 mN in the unstable and stable patients, respectively. ET-1 caused a concentration-dependent contraction of the IMA in the unstable and stable groups (Fig. 3) . Incubation with 10-5 M of BQ-123 almost completely abolished the response to ET-1 in both groups (Fig. 3). Similarly, Big ET-1 caused a BQ-123 (10-5 M) sensitive concentration-dependent contraction of the IMA in both groups (Fig. 4) .



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  		Fig. 3. Contractile effects of ET-1 alone in IMAs in unstable (open squares) and stable (black squares) patients and with incubation with BQ-123 (10-5 M) in unstable (open triangles) and stable (black triangles) patients. Data are presented as means±SEM and are expressed as a percentage of the maximal contraction induced by a 127 mM concentration of K+.

 


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  		Fig. 4. Contractile effects of Big ET-1 alone in IMAs in unstable (open squares) and stable (black squares) patients and with incubation with BQ-123 (10-5 M) in unstable (open triangles) and stable (black triangles) patients. Data are presented as means±SEM and are expressed as a percentage of the maximal contraction induced by a 127 mM concentration of K+.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
In this study, the plasma levels of ET-1 were lower, whereas the pre-operative levels of Big ET-1 were higher, in patients with unstable angina pectoris than in those with stable angina. Following revascularization, ET-1 initially increased in both groups after the operation followed by a slow decrease with a tendency of equalization of the ET-1 levels between the groups. A decrease of Big ET-1 was observed in the unstable group with levels similar to those of the stable patients at 14 h after the operation.

The increased levels of Big ET-1 in the plasma of unstable patients is in accord with several other studies [12,13]. It has also been demonstrated that ET-1 levels are unchanged or decreased in unstable patients [12,14,15,17], although some authors report an increased ET-1 level in unstable patients [13,16,18]. Lower ET-1 and higher Big ET-1 levels in unstable patients in comparison with patients with stable angina were confirmed in our study. The relation between ET-1 and Big ET-1 in the unstable patient group could be explained by an increased turnover of ET-1 resulting in a increase in Big ET-1 synthesis, which may be related to differences in ET converting enzyme activity between these agents. Although the ET-turnover may be influenced pharmacologically, variability in patient medication in the studied groups could not explain the presently observed differences in circulating ET-1 levels in the stable and unstable patients. The hypothesis regarding an increased turnover of ET-1 is supported by Brehm [12], who not only showed an increased level of Big ET-1 and an unchanged level of ET-1 in unstable patients, but also demonstrated that a venous occlusion test increased circulating ET-1 levels in stable patients but not in unstable patients, thereby indicating an increased turnover of ET-1 which could not be raised by additional provocation. However, the surgical intervention in our study caused a further increase in ET-1 levels in both the stable and unstable patient groups, although Big ET-1 levels were further increased only in the stable group. The source of the increased plasma levels of ET-1 and Big ET-1 prior to and immediately after revascularization is unclear [21]. To what extent the cardioplegic solution, the use of the heart–lung machine or the cardiac ischaemia causes ET-1 and Big ET-1 levels to increase remains to be established [22,23]. Revascularisation of the unstable patients caused a return of Big ET-1 to the same levels as in the operated stable patients. A similar tendency was seen with ET-1 levels in the unstable patients with a return to the level of the stable patients following surgery. This suggests that the pre-operative imbalance of Big ET-1 and ET-1 in the unstable patients is caused by the inadequate blood supply to the heart.

It was further demonstrated that the pericardial concentration of ET-1 in the unstable group was significantly lower compared with the stable group, corresponding to the differences in plasma between the groups. Although there were no significant differences in Big ET levels, these findings corroborate with the hypothesis of increased ET-1 turnover in unstable angina pectoris. Pericardial fluid is mainly formed as a passive ultrafiltrate of blood plasma, which indicates that the plasma is the major source of pericardial ET-1 content. However, a contributing source of ET-1 could be the epicardium itself, since epicardial mesothelial cells have been shown to secrete ET-1 in vitro [24]. Pericardial ET-1 levels have been suggested to provoke cardiac arrythmias [25] and may therefore add to the unstable condition in these patients.

More than 90% of ET has been estimated to be released abluminally [26], i.e. towards the smooth muscle cells, and therefore plasma levels may represent only a portion of released peptide. We could not distinguish any differences in IMA content of ET-1 in stable and unstable patients in spite of higher plasma levels in stable patients. However, ET-1-receptor subpopulations and turnover were not determined in these patients and further characterization of vascular ET-effects remains to be done.

In the present functional experiments, the IMA was examined, not only because this is the principal artery used as a graft in CABG, but also because the IMA has previously been shown to contain similar ET levels as coronary arteries, and to react very similar to coronary arteries when exposed to ET-1 stimuli [6]. Both ET-1 and Big ET-1 evoked comparable concentration-dependent vasoconstriction of IMAs from both unstable and stable patients. Interestingly, coronary artery disease is associated with augmented ET-1-induced vasoconstriction directly related to the severity of disease [27]. The present findings therefore support that the IMA is equally well suitable for grafting in stable and unstable patients. Addition of the selective ETA-blocker BQ-123 almost completely inhibited the constrictive effect of ET-1 as well as that of Big ET-1 in both groups, indicating that ETA-blockade is sufficient to reverse ET-induced coronary vasoconstriction [6]. This finding also suggests the possible use of ET-blockade to prevent post-operative ET-1-induced constriction of the IMA in CABG in both groups.

It is concluded that unstable angina pectoris is associated with an increased ET-1 turnover. This increased turnover may participate in the local regulation of coronary vascular tone with influence on the condition of the patient. The present investigation also suggests that ETA-blockade may be useful as an additional pharmacological principal in the treatment of unstable angina pectoris prior to revascularization.


   Acknowledgments
 
Supported by grants from the Swedish Heart and Lung Foundation, the Janne Elgqvist Foundation, the Wallenberg Foundation, the Serafimer Lasarettet Foundation and funds from the Karolinska Institute.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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