Perioperative Thromboxane Changes in Cardiac Risk Patients
Version 1.3 First Published 12.10.99
Wolfgang Sametz, Helfried Metzler*, Elisabeth Mahla*, Heinz Juan
Department of Biomedical Research and the Department of Anaesthesiology*, University of Graz, Austria.
Corresponding author: Wolfgang Sametz, Department of Biomedical Research, University of Graz, Roseggerweg 48, A-8036 Graz, Austria. Phone: 0043-316-385/3955; FAX: 0043-316-385-3956; E-mail: firstname.lastname@example.org
It was found previously that in cardiac risk patients undergoing non-cardiac surgery, postoperative cardiac complications were correlated with high postoperative serum levels of troponin T (TNT) and troponin I (TNI). We investigated whether perioperative changes in the release of thromboxane A2 (TXA2), measured as TXB2, correlate with the increased serum level of TN (TN).
Plasma levels of TXB2 were determined in 40 patients at risk for, or with definite coronary artery disease. Blood sampling was performed in the morning on the day before surgery, on the day of surgery before induction of anesthesia and until the fifth postoperative day for measurement of TXB2 by specific radio-immunoassay.
The plasma concentration of TXB2 was significantly higher in TN patients (200±14 pg/ml) preoperatively compared with that in patients with low TN release (TN0) (150±7 pg/ml) and the concentration was much higher in all cardiac risk patients than in healthy volunteers (67±7 pg/ml). TXB2 plasma level decreased significantly on the 2nd and 3rd postoperative days in TN patients (140 ± 17 pg/ml and 142 ± 16 pg/ml, respectively). In contrast, no significant changes in plasma concentration of TXB2 took place perioperatively in TN0 patients.
This study demonstrates that the high preoperative TXB2 plasma concentration as an indication of enhanced platelet activity correlates with high postoperative serum levels of troponins in cardiac risk patients undergoing non-cardiac surgery.
For several years, in cardiac risk patients undergoing non-cardiac surgery, the perioperative pattern of myocardial ischemia has been investigated by various authors (Fleisher et al, 1995; Mangano et al, 1991; Mangano and London, 1991; Metzler et al, 1991; Raby et al, 1992). Postoperative ischemia seems to correlate with adverse outcome, and prolonged subendocardial ischemia rather than acute coronary artery occlusion precedes cardiac complications (Fleisher et al, 1995; Landesberg et al, 1993).
Cardiac troponins - troponin T (TNT) and troponin I (TNI) - have been established as a sensitive marker for detection of major and minor myocardial cell injury, avoiding the high incidence of false positive results by the use of creatine kinase (CK)-MB
(Adams et al, 1994; Katus et al, 1991; Lee et al, 1996). Metzler et al (1997) found that in cardiac risk patients undergoing non-cardiac surgery high postoperative levels of TNT and TNI were correlated with postoperative cardiac complications, whereas patients with no or only slightly increased concentrations of both troponins (TN) had a good outcome.
Platelet activation accompanied by an increased TXA2 synthesis occurs in patients with peripheral arterial disease or ischemic heart disease (FitzGerald et al, 1983; FitzGerald et al, 1986; Metha and Metha, 1977; Trip et al, 1990; Lorenz and Weber 1992). Intact vascular endothelium plays an important role in the defense against platelet aggregation and vasospasm by its ability to release vasodilators like nitric oxide (NO) (Furchgott and Vanhoutte, 1989; Moncada et al, 1988). A decrease in the release of NO appears to occur at an early stage in the atherosclerotic process (Vanhoutte and Shimokawa, 1989). In atherosclerotic vessels, endothelial damage or dysfunction impair the protective functions of NO and favour vasoconstriction and further platelet aggregation by enhanced release of vasoconstrictors like TXA2 (Mügge et al, 1991, Flavahan, 1992).
In view of these findings, the aim of this study was to investigate whether perioperative changes occur in the release into the plasma of the cyclooxygenase product TXA2 and whether the level of this endogenous vasoactive substance is correlated with the enhanced serum level of TN and/or with postoperative cardiac complications. Therefore, we determined the plasma concentration of TXB2 , the stable metabolite of TXA2 , as an in vivo index of platelet activation in 40 cardiac risk patients out of 67, which were included in the study of Metzler et al (1997).
Abbreviations used in this paper: TN, enhanced release of troponin; TN0, low or no release of troponin
The investigation conforms with the principles outlined in the Declaration of Helsinki and after obtaining approval from the Medical Ethics Committee of the University, we investigated 40 cardiac risk patients undergoing elective non-cardiac surgery. Subjects were included in the study according to the presence of definite coronary artery disease (CAD) or were at risk for it. Definite CAD was defined as previous myocardial infarction (MI), typical or atypical angina with positive exercise testing or scintigraphic evidence, or previous coronary artery bypss grafting (CABG) or pericutaneous transluminal coronary angioplasty (PTCA). Patients at risk for CAD were included, if they had at least three of the following cardiac risk factors:
Age > 65 yr, hypertension, current smoker, treated diabetes mellitus (insulin or oral
hypoglycaemic agents), increased serum cholesterol concentration (>5.7 mmol /l ) or previous vascular surgery. Clinical data are summarized in table 1.
Before operation, patients were clinically evaluated; this included 12-lead ECG, chest x-ray and echocardiagraphy. Premedication, anesthesia and postoperative care were performed by clinicians not involved in the study and blinded to all research information. Twelve-lead ECG recordings were performed daily in the morning together with blood sampling for determination of TNT, TNI, TXB2 and blood cells count on the day before surgery (day -1), on the day of surgery before induction of anesthesia (day 0) and until the fifth postoperative day (1-5 day). Methods of determination of TNI and TNT were described by Metzler et al. (1997) previously.
TNT-values greater than or equal to 0.2 ng/ml and TNI-values greater than or equal to 0.6 ng/ml were considered as TN positive (Metzler et al, 1997; Hamm et al, 1992).
These data served as the basis for the present study. For these investigations determination of the TXB2 plasma concentration was performed in 40 patients out of the 67. Six patients received aspirin (100 mg/day) preoperatively until the 5th day before surgery. 22 vascular surgery patients received a single dose of 1.0 g aspirin i.v. on day 0 after operation and on the first postoperative day. On the following days aspirin at a dose of 100 mg/day was administered p.o.
Plasma was prepared by centrifuging citrated venous blood (3.8 % Na citrate) at 3000 rpm for 10 min. Blood vials contained 1 µg/ml indomethacin to prevent further TXA2 synthesis. The plasma was acidified to 3 or 4 with HCl and then extracted with 3 volumes of ethyl acetate. The organic phase containing thromboxane was evaporated and the residue redissolved in buffer. TXA2 was measured as its stable product TXB2 by specific radio-immunoassay (Advanced Magnetics Inc. Cambridge, Massachusetts, USA).
The TXB2 concentration in plasma of healthy volunteers collected into vials containing acetylsalicylic acid was about 70 pg/ml (Viinikka and Ylikorkala, 1980).
An adverse cardiac outcome was defined as the occurrence of unstable angina, severe cardiac arrhythmias compromising cardiovascular status, decompensated congestive heart failure (CHF), MI or cardiac death. MI was diagnosed using the
following criteria: CK-MB>12 iu/l and in the electrocardiogram the development of either new Q-waves or persistent ST-elevation in the 12-lead ECG.
The determination of erythrocyte count, leucocyte count and thrombocyte count was performed by routine laboratory methods.
Values are expressed as means ± SEM. Statistical significance was calculated using the unpaired Student´s t test to compare data between the TN and TN0 groups. Comparison of variables within groups was made by analysis of variance for repeated measures followed by Student-Newman-Keuls multiple comparison test. P < 0.05 being accepted as level of significance.
Adverse cardiac outcome
No release of both TN was observed preoperatively. The cutoff values of increased postoperative TN release were exceeded in 9 (22.5 %) patients, whereby 5 (12.5%) had cardiac complications between the 3rd and 4th postoperative day with TNT values between 0.4 and 7.0 pg/ml and with TNI values between 0.8 and 24.4 pg/ml serum: Two patients suffered from unstable angina; in one patient congestive heart failure occurred; one patient developed malignant arrhythmias and another postoperative non-Q-wave infarction. The four TN patients without cardiac complications showed TNT values between 0.26 and 0.47 pg/ml and TNI values between 0.7 and 4.2 pg/ml serum. The maximum increase of TNI occurred on the second or third, and that of TNT on the 4th or 5th postoperative day. Patients with no or only slightly increased TN concentrations (TN0) had no postoperative cardiac complications.
The plasma concentration of TXB2 was significantly higher in TN patients (200±14 pg/ml) preoperatively compared with that in TN0 patients (150±7 pg/ml) and the concentration was extremly elevated in all cardiac risk patients in comparison to the healthy volunteers (67±7 pg/ml) (Fig.1). The preoperative plasma level of TXB2 was190 pg/ml or higher in the 5 TN patients with an adverse outcome. In 2 TN patients with a good outcome plasma level was 160 pg/ml and in two 190 pg/ml. In three TN0 patients TXB2 reached a concentration of 190 pg/ml preoperatively. In all other 28 patients the plasma level was below 190 pg/ml (80-180 pg/ml). TXB2 plasma level increased slightly but not significantly on the 1st postoperative day followed by a significant decrease on the 2nd and 3rd day in TN patients (140±17 pg/ml and 142±16 pg/ml, respectively). TXB2 increased significantly again to preoperative values on the 4th postoperative day (204±16 pg/ml) and decreased on the 5th day to the level of the 2nd and 3rd day (Fig.1), whereby the decrease on the 5th day depended on the low TXB2-values of the patients with an adverse cardiac outcome. The TXB2 values (128±3 pg/ml) on the 5th day of the five TN patients with an adverse cardiac outcome were significantly lower than that of the four TN patients with a good outcome (190±11 pg/ml). In TN0 patients the plasma level of TXB2 showed only a slight not significant decrease on the 2nd and 3rd postoperative day and returned to preoperative values on the 4th and 5th day (Fig. 1).
Blood cell count
Blood cells count is summarized in table 2. Erythrocyte count was slightly reduced postoperatively in both groups. Leucocyte count was significantly enhanced postoperatively in both groups, whereby the values remained significantly enhanced until the 5th day in TN patients. The leucocyte count in TN0 patients returned to preoperative values on the 3rd postoperative day. Thrombocyte count was reduced significantly in both groups, whereby the decrease reached its maximum (about 25 %) on the 3rd postoperative day in TN patients and on the 2nd day (about 10 %) in TN0 patients.
As reported previously it was found that in cardiac risk patients undergoing non-cardiac surgery postoperative cardiac complications were correlated with high postoperative serum levels of TNT and TNI, whereas patients with no or only slightly increased concentrations of both TN had a good outcome (Metzler et al, 1997). In the present study, we investigated whether TXA2 release (measured as TXB2 ), as an in vivo index of platelet activation, correlates with enhanced release of TN and take part in the adverse cardiac outcome of the TN patients.
TXA2 , one cyclooxygenase product of arachidonic acid derived from platelets, is a potent vasoconstrictor, an agonist of platelet aggregation as well as an arrhythmogen (Moncada and Vane, 1979; Weber et al, 1982; Schrör and Hohlfeld, 1990).
Vasodilators such as NO released from intact vascular endothelium antagonize the effects of TXA2 (Furchgott and Vanhoutte, 1989; Moncada et al, 1988). Endothelial damage or dysfunction impair this protective mechanism and favour vasoconstriction and enhanced platelet aggregation in atherosclerotic vessels (Mügge et al, 1991; Lopez et al, 1989). This enhanced platelet activity is accompanied by an increased TXA2 synthesis. Also cholesterol, which is increased in atherosclerotic patients, seems to increase platelet aggregability by stimulating platelet TXA2 production Stuart et al, 1980). Platelet activation occurs in patients with peripheral arterial disease, unstable and stable angina or acute MI (FitzGerald et al, 1983; FitzGerald et al, 1986; Metha and Metha, 1977; Trip et al, 1990; Lorenz and Weber 1992).
All these facts lend TXA2 formation pathophysiological importance, with diagnostic potential in cardiovascular disease.
The results of the present study show that preoperative TXB2 plasma concentration was increased significantly in cardiac risk patients in comparison to healthy
volunteers. This was not surprising, because the patient's histories show that 88%
had an increased cholesterol level, 88% suffered from angina pectoris, 7% from unstable angina and 70% had a previous MI. The TXB2 plasma concentrations of the healthy volunteers as well as of the cardiac risk patients are in agreement with Hirsh et al (1981), who found about 70 pg/ml plasma in healthy volunteers and about 180 pg/ml plasma in patients with ischemic heart disease.
An interesting result was the significantly higher amount of TXB2 in TN patients compared with that in TN0 patients preoperatively, although no enhanced preoperative TN level was observed in either patients group. It is well documented that aspirin suppresses TXA2 synthesis and inhibits platelet aggregation (Burch et al, 1978; Masotti et al, 1980; Patrono et al, 1985). Therefore, it is an important therapeutic strategy today to use these beneficial effects of low doses of aspirin in patients with ischemic heart diseases or peripheral vascular disease (Magnani and Semprini, 1994; Ranke et al, 1994). A single dose of 100 mg aspirin causes already an irreversible inhibition of platelet cyclooxygenase and therefore, only new platelets can recover enzymatic activity (platelet turn-over 8 days) (Montalescot, 1995). Only three of the TN and three of the TN0 patients received a single dose of 100 mg/ day aspirin until the 5th preoperative day. All other patients received no aspirin or the treatment was stopped earlier. Therefore, we can assume that the difference in the amount of TXB2 release between the two groups is not due to an inhibition of cyclooxygenase. It is assumed that chronic hyperreactivity of platelets plays an important role in the progression of peripheral arterial and coronary arterial disease (Adam et al, 1987, Reininger et al, 1994). Eight of the nine TN patients with increased preoperative TXB2 concentration and 14 patients (44%) in the TN0 group with significantly lower TXB2 concentrations suffered from peripheral arterial occlusion and underwent vascular surgery in the present study. In view of these results, we can speculate that enhanced TXB2 values together with vascular surgery could be considered as an additional indication of high risk for patients to suffer from cardiac complications postoperatively.
The TNpatients, who suffered from peripheral arterial occlusion, received aspirin postoperatively. Though, the one TNpatient, who underwent abdominal surgery, received no aspirin and showed the greatest decrease on the 2nd and 3rd postoperative day (from 220 pg/ml on the 1st day to 57 on the 2nd and 47 pg/ml on the 3rd). No difference existed also between the TXB2 release pattern of the aspirin treated (44%) and of the untreated TN0 patients. Therefore, it seems that the significant decrease of TXB2 on the 2nd, 3rd and 5th postoperative days is independent of administration of aspirin. The significant decrease of TXB2 in TNpatients and the slight in TN0 patients was accompanied by a decrease in platelet count on the 2nd and 3rd postoperative day. A significant increase in platelet activity and a concomitant decrease in platelet count were observed after vascular surgery (Reininger et al, 1992; Reininger et al, 1994).These effects were not influenced by aspirin and were also not due to blood loss (Reininger et al, 1992; (Reininger et al, 1994).The authors assumed that the reduction in the platelet count might be due to a destruction of platelets induced by the enhanced platelet adhesivity and aggregability. Although in our study the platelet count was more reduced in TN patients (about 24%) than in TN0 patients (about 10%), it is unlikely that the decrease of TXB2 depends on this fact, because the decrease on the 5th day in TN patients was not accompanied by a decrease in platelet count. The hypothesis that enhanced TXA2 production inactivates human platelet TX-synthase and is therefore self-limiting (Hall et al, 1986; Jones and Fitzpatrick, 1991) is more likely responsible for the significant decrease of TXB2 on the 2nd, 3rd and 5th postoperative day. No difference existed between the decrease in the TN patients with an adverse cardiac outcome and in the TN patients with a good outcome on the 2nd and 3rd day. In contrast to this decrease, which seems to be a consequence of enhanced platelet activity after operation, the decrease of TXB2 concentration on the 5th day depended on the low TXB2-values of the patients with a cardiac complication.
It was found that enhanced platelet activity is associated with recent episodes of angina in patients with unstable angina pectoris (Hirsh et al, 1981). If a self limiting process is responsible for the decrease of TXB2 release, we can speculate that the decrease on the 5th postoperative day is a consequence of a cardiac event. Taken together all these facts, we can assume that enhanced platelet activity is involved in the occurrence of postoperatve cardiac complications.
Additionally, we can assume that the deleterious role of increased synthesis of TXA2 in propagation of myocardial ischemic injury (Haerem, 1972) might contribute to the postoperative increased release of TN.
In recent years it was found that prostaglandin isomers, the so-called isoprostaglandins (isoP) and also isothromboxane (isoTX), are formed in vivo by free radical catalyzed peroxidation of arachidonic acid independent of cyclooxygenase activity in humans and animals and can be detected in plasma and urine
(Morrow et al, 1990; Morrow et al, 1994; Morrow et al, 1996). Compared with the traditional prostaglandins PGF2a and PGE2, which are weak vasoconstrictors, isoprostaglandin F2a (F2-isoP) and isoprostaglandin E2 (E2-isoP) are potent vasoconstrictors in vivo and in vitro at similar concentrations (RobertsII and Morrow, 1997). Low nanomolar subthreshold concentrations of F2-isoP and E2-isoP amplified the vasoconstrictor response of norepinephrine or angiotensin II in vitro ( Sametz et al, 1999). Free radicals play an important role in the pathophysiology of a wide spectrum of diseases including atherosclerosis, ischemia-reperfusion injury, inflammatory diseases and cancer (halliwell and Grootveld, 1987; Ross, 1986). Enhanced F2-isoP was detected in human atherosclerotic lessions and plaques and was generated during cornary reperfusion (Pratico et al, 1997; Delanty et al, 1997) and in patients with hypercholesterolemia (Davi et al, 1997). This suggests that isoP, including isoTX, could be formed also in cardic risk patients. Moreover, it was found that antibodies used in immunoassays for cyclooxygenase-derived prostaglandins exhibit cross-reactivity with isoP (Morrow et al, 1990; Proudfoot et al, 1995). We can speculate that also the TXB2 antibody, which was used in the present study, cross-reacts with isoTX, and therefore a part of the measured TXB2 concentration might be due to the release of isoTX.
This study demonstrates that the high preoperative plasma concentration of TXB2 as an indication of enhanced platelet activity correlates with high postoperative serum levels of troponins in cardiac risk patients undergoing non-cardiac surgery.
The high portion of vascular surgery patients in the group with increased TXB2 and TN may illustrate the role of peripheral and coronary artery disease as a causative or contributing mechanism.
The determination of isothromboxane could be of interest in the future, if selective assays become available for diagnostic purposes. In regard to their vasoconstrictor effects and as a marker of oxidative injury, isoprostaglandins, including isothromboxane, could play an important role in cardiovascular diseases and could possibly serve as an additional preoperative risk indicator.
Acknowledgement The study was supported by a grant from the Austrian National Research Foundation (P09172 Med)
TABLE 1 Clinical data for the 40 patients
|Age < 65 yr||24 (60)|
|Sex (M/F)||30/10 (75/25)|
|Diabetes mellitus||7 (18)|
|Current smoking||17 (43)|
|Increased cholesterol||35 (88)|
|Cardiac history||No. of Patients (%)|
|Angina pectoris||35 (88)|
|Unstable angina||3 (7)|
|Previous MI||28 (70)|
|History of congestive HF||5 (13)|
|Previous CABG||5 (13)|
|Previous PTCA||7 (17)|
|Preoperative cardiac medication|
|Calcium antagonists||14 (35)|
|ß-adrenergic blockers||5 (13)|
|ACE inhibitors||12 (30)|
|Type of surgery|
|Type of anaesthesia|
Patients with enhanced troponins (TN); patients without or with low troponins (TN0).
x p < 0.05 TN vs TN0; # p < 0.05; ## p < 0.01 preoperatively vs postoperatively.
|time (days)||TN TN0||TN TN0||TN TN0|
|(n=9) (n=31)||(n=9) (n=31)||(n=9) (n=31)|
|- 1st||4.50 4.80||7.9 7.8||284 234|
|±0.14 ±0.10||±0.5 ±0.3||±28 ±8|
|0||4.36 4.68||7.1 6.8||270 229|
|±0.70 ±0.08||±0.6 ±0.3||±25 ±8|
|1st||4.05 4.17||10.8 9.6||233 208#|
|±0.15 ±0.10||±0.7## ±0.3##||±22 ±7|
|2nd||3.93 4.03||11.6 10.2||216# 207#|
|±0.21 ±0.10||±0.9## ±0.4##||±19 ±8|
|3rd||3.88 3.87||10.0 8.0||214# 217|
|±0.16 ±0.15||±0.7x# ±0.3||±20 ±8|
|4th||3.84 3.87||9.3 7.2||255 237|
|±0.16 ±0.10||±0.7x# ±0.2||±29 ±8|
|5th||3.91 3.90||9.0 7.0||268 240|
|±0.12 ±0.09||±0.7x# ±0.3||±26 ±10|
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Figure 1. Plasma concentration of thromboxane B2 expressed as mean ± SEM calculated from 9 TN patients ( ), 31 TN0 patients ( ) and from 10 healthy volunteers ( ). **P < 0.01 TN vs TN0 patients; ##P < 0.01 preoperatively vs postoperatively; §P < 0.05 third vs fourth postoperative day.