Eur J Cardiothorac Surg 2004;25:772-778
© 2004 Elsevier Science NL
Chronic stable ischaemia protects against myocyte damage during beating heart coronary surgery
Gerald Carr-White1,
Tat Koh,
Anthony DeSouza,
Elizabeth Haxby,
Michael Kemp,
James Hooper,
Derek Gibson,
John Pepper*
Departments of Academic Cardiac Surgery, Cardiology, Biochemistry and Anaesthesia, Royal Brompton and Harefield Hospitals NHS Trust, Sydney Street, London, UK
Received 6 August 2003;
received in revised form 28 January 2004;
accepted 11 February 2004.
* Corresponding author. Address: Cardiothoracic Surgery, National Heart and Lung Institute, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel./fax: +44-0207-351-8530
e-mail: g.carr-white{at}virgin.net
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Abstract
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Objectives: Many patients with coronary artery disease demonstrate chronic resting ischaemic myocardial dysfunction. We have investigated whether this ischaemia influences the myocardial damage caused by the period of coronary occlusion involved in beating heart surgery. Methods: Thirty-three patients with chronic stable angina and normal left ventricular ejection fraction were studied. To make our model clinically appropriate, we included patients with a wide range of ischaemic times, ages and in a subset of 10 patients a surgical preconditioning protocol. Myocyte injury was assessed from venous Troponin T release measured on days 1, 2, and 3. We used intraoperative transoesophageal M mode echocardiograms and simultaneous high-fidelity left ventricular pressure to assess whether patients were demonstrating the functional effects of ischaemia (asynchronous regional contraction with reduced mechanical function). Results: Patients demonstrated the functional effects of resting ischaemia and 17 did not. Patients with resting ischaemia had lower preoperative values of regional peak power and work and all three variables increased significantly with surgery. Venous Troponin T levels at 48 and 72 h postoperatively were lower in those with preoperative resting ischaemia (median (interquartile range) 0.13 (0.08–0.20) vs 0.21 (0.13–0.69) for 48 h and 0.10 (0.08–0.19) vs 0.26 (0.12–0.51) for 72 h). Stepwise multiple linear regression of total postoperative troponin release (measured as the area under the curve of troponin release) demonstrated two independent determinants (R squared for model 0.40): longer ischaemic time, and increasing values of cycle efficiency. The surgical ischaemic preconditioning protocol and preoperative collaterals were not independent determinants. Conclusions: In patients with chronic coronary artery disease, stable preoperative ischaemia may thus represent a naturally occurring form of myocardial protection, whose presence reduces Troponin T release after beating heart surgery. This protection is different in nature from classical ischaemic preconditioning.
Key Words: Beating heart coronary artery surgery • Left ventricular function • Synchrony • Preconditioning • Troponin T
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1. Introduction
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In humans with chronic angina the pattern of mechanical activity is often modified in regions whose blood supply is compromised, so that resting values of peak power and work are reduced even in the absence of overt ischaemia, and are promptly reversed by revascularisation [1]. This stable reduction in mechanical activity might be considered a form of adaptation such that reduced mechanical activity is matched with perfusion. We hypothesized that it might act as an endogenous protection mechanism. We, therefore, set out to assess whether this preoperative adaptation modifies myocardial injury, by using Troponin T release as an index of myocardial damage in patients undergoing warm regional ischaemia during beating heart coronary surgery [2–5]. In order to put any findings into their relevant clinical context we included in our model a wide range of ages and ischaemic times (by using patients receiving 1, 2 or 3 bypass grafts) and, in a subset of patients, a standard surgical method of ischaemic preconditioning [6]. These three factors are known to be important determinants of myocyte damage.
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2. Materials and methods
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2.1. Patients
We studied 33 patients (mean age 65 (9) years; 25 men) undergoing coronary artery surgery without cardiopulmonary bypass using the ‘Octopus II’ myocardial stabilisation device. All the patients had chronic stable angina. Demographics and preoperative treatment are given in Table 1. Twenty-one patients had stenoses of greater than 70% in both the left anterior descending artery and the right coronary artery and of these, 10 patients (age 64 (7) years, 6 male) were randomised to ischaemic preconditioning and 11 (age 61 (9) years, 7 male) were not. Five remaining patients underwent a single graft to the left anterior descending artery and seven underwent grafts to all three major coronary arteries. Only patients with normal left ventricular function were included, as defined by both normal ejection fraction (>55%) measured by prior contrast angiography in the right anterior oblique view and the absence of regional wall motion abnormalities both on angiography and transoesophageal echocardiography. No patient had evidence of previous myocardial infarction either on electrocardiography or from wall motion abnormalities on echocardiography. Patients taking nicorandil were excluded from the study. The investigation conforms with the Declaration of Helsinki 2000. The protocol had been approved by the Research Ethics Committee of the Royal Brompton and Harefield Hospital NHS Trust and written informed consent was obtained from all patients. There were no complications of the study.
2.2. Operative procedure
General anaesthesia was induced by etomidate, fentanyl and pancuronium administered intravenously, and maintained by inhaled isoflurane in an oxygen:air mix (50:50) according to a standardised protocol. The operation was performed through a median sternotomy. After harvesting the bypass conduits, heparin was given at a dose of 100 iu/kg. The ‘Octopus II’ device (Medtronic Inc, Grand Rapids, Michigan, USA) was used to immobilise the region on either side of the coronary artery to be grafted and has been described in detail elsewhere [7]. 2/0 prolene sutures were used as snares to occlude coronary flow proximal and distal to the site of anastomosis to allow grafting of the artery in a bloodless field. Intraluminal coronary shunts were not used. When the anastomosis was complete, the coronary snares were released to restore coronary blood flow. In all patients the left anterior descending artery was grafted with a pedicled left internal mammary artery. The right coronary artery was grafted with reversed saphenous vein in 10 patients and a radial artery in 18. In seven patients the circumflex artery was grafted with reversed saphenous vein.
2.3. Assessment of collateral supply
Coronary angiograms were reviewed and collateral vessels to each grafted coronary artery were graded by scoring the amount of dye reaching the target artery from injections into the other coronary arteries [8]: 0, no filling of collateral vessels; 1, filling of collateral vessel without any epicardial filling; 2, partial epicardial filling; 3, complete epicardial filling. A collateral score was then calculated by dividing the sum of the grades for each grafted artery by the number of grafts.
2.4. Preconditioning protocol
The preconditioning protocol was adapted from that previously described by Jenkins and Yellon [9]. Immediately before each coronary artery was grafted, the coronary snares were applied to generate two periods of 3 min of complete occlusion before that needed for coronary grafting itself, with 2 min uninterrupted flow between them.
2.5. Echocardiographic protocol
A 5 MHz multiplane transoesophageal probe was inserted after induction of anaesthesia and connected to a Hewlett Packard Sonos 2500 echocardiographic system. The electrocardiogram was monitored with the V5 chest lead. After opening the pericardium a 4F catheter tip manometer was introduced into the left ventricular cavity via the roof of the left atrium and its output filtered (1 KHz) preamplified, and transferred to the auxiliary channel of the echocardiographic system. The pressure transducer was calibrated electrically before the initial measurement and was checked against an air operated dead weight balance (Budenberg Gauge Company Ltd, Altringham, Cheshire, England) after the study. The zero point for pressure measurement was taken as atmospheric. At the end of the study, the catheter tip manometer was removed and the exit site at the roof of the left atrium closed with a purse string suture.
2.6. Echocardiographic methods
A transoesophageal transgastric view of the left ventricular cavity in transverse section was obtained, and M mode recordings of the left ventricular cavity at papillary muscle level made simultaneously with the left ventricular pressure trace. Recordings were made at paper speed of 100 mm/s, when the patient was in a stable condition after sternotomy and pericardotomy (baseline) and 30 min after release of the last coronary snare (post). The endocardial and epicardial boundaries of the anterior and posterior wall of the M mode echograms were digitised off-line together with the left ventricular pressure trace. The digitising system had a sampling velocity of 100/s and three cardiac cycles were digitised. For measurements of left ventricular dimensions, the onset of the Q wave of the electrocardiogram was taken as left ventricular end diastole, and end systole was taken as the point of maximal velocity of decline of left ventricular pressure [10].
2.7. Assessment of regional LV function
From the digitised, continuous plots, loops of LV anterior wall thickness were derived, along with its rate of change. At any instant, myocardial power (mW/cm2) of endocardium is given by the product of thickening rate and ventricular pressure. The positive (systolic) portion of this trace was integrated with respect to time to give myocardial work (mJ/cm2) (Fig. 1a)
. Finally, pressure-anterior wall thickness loops were constructed (Fig. 1b). The ratio of the loop area to that of the rectangle that just encloses it represents cycle efficiency, a measure of regional coordination [6,7,11,12]. All values were taken as the mean of three beats. Haemodynamic measurements including heart rate, mean arterial blood pressure and right atrial pressure were also recorded.
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Fig. 1. (a) A normal regional myocardial power trace plotted throughout the cardiac cycle showing how peak power and myocardial work are calculated. (b) A normal pressure-wall thickness loop showing how cycle efficiency is calculated.
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2.8. Division of patients by cycle efficiency
Cycle efficiency has proved a very sensitive marker of regional myocardial ischaemia [6,7]. The patients were, therefore, divided according to their preoperative cycle efficiency into those above and below the median level of 70%. Seventeen patients (age 64 (9) years, 12 male) had a CE>70% (the non-ischaemic group), and in 16 patients (age 60 (5) years, 13 male) the CE was <70% (ischaemic group). There were no differences between the two groups with regard to preoperative drug regime, ejection fraction, collaterals or angina score (Table 1).
2.9. Troponin T measurements
Peripheral venous blood samples were obtained preoperatively and then 24, 48 and 72 h after the operation for Troponin T estimation. All samples were centrifuged within 20 min and the plasma was stored at –20 °C until analysis. Troponin T release was measured as the concentration in peripheral venous blood in micrograms per litre.
2.10. Biochemical analysis
Cardiac Troponin T was measured using a commercially available enzyme linked immunosorbent assay kit (ELISA Troponin T, Boehringer Mannheim) and batch ELISA analyser (Enzymun test system ES 300, Boehringer Mannheim). The Troponin T ELISA used [15] had a lower detection limit of 0.05 µg/l, and concentrations above the discriminator value of 0.1 µg/l were considered elevated [16,17]. Coefficient of variation for Troponin T measurements was 7% for concentrations between 0.1 and 2 µg/l.
2.11. Statistical analysis
2.11.1. Echocardiographic variables
Results are presented as mean (SD). Unpaired t-tests were used to compare differences between groups and variables at the two time points were compared using paired t-tests. A Bonferroni correction was used to allow for multiple comparisons where appropriate.
2.12. Troponin T values
The results are presented as median and interquartile range (25–75%) and non-parametric statistical tests used, as normal distribution could not be assumed. A Mann–Whitney test was used to compare two groups. Paired samples were analysed using a Wilcoxon matched pairs test. For more than two groups, a Kruskal–Wallis test was used, and if significant a Dunn's test to compare groups. For paired data at more than two time points, a Friedman test was used. The level of significance was taken as P<0.05. Further analysis of determinants of Troponin T release was carried out using a stepwise multiple linear regression model.
2.13. Reproducibility
This was assessed by redigitising traces from a random sample of 10% of the beats after a period of 3 months. The variables assessed include left ventricular end diastolic and end systolic dimensions, cycle efficiency, myocardial work and peak power. The root mean square difference between duplicate measurements and the values for coefficient of variation derived from the ratio of the root mean square difference and absolute value were determined.
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3. Results
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3.1. Clinical and electrocardiographic data
All patients were successfully grafted without cardiopulmonary bypass and no patient required inotropic support or pacing postoperatively. Mitral regurgitation was not detected on colour flow mapping pre or postoperatively in any patient, and none showed evidence of perioperative myocardial infarction on the basis of electrocardiography or creatine kinase levels. Coronary snare times for each individual grafted artery ranged between 9 and 16 min (mean 13 min). Ischaemic times, representing the sum of the ischaemic times for each artery, ranged between 12 and 52 min (mean 32 min). Haemodynamic variables were similar pre and postoperatively (heart rate 82 (9) vs 84 (8), mean arterial pressure 74 (6) vs 71 (9), right atrial pressure 8 (4) vs 10 (5)) (P, ns for all). All patients were in sinus rhythm pre and postoperatively.
3.2. Troponin T release
Before surgery, the Troponin T concentrations were below the detectable range of the assay (<0.05 µg/l) in all patients. Postoperatively, raised Troponin T levels were consistently seen up to 72 h, indicating some degree of myocyte injury. Samples less than 24 h after surgery were not analysed as earlier peaks are unrelated to myocardial damage, but represent leakage from the unbound cytoplasmic pool [13,14]. When the Troponin levels were analysed by cycle efficiency (Fig. 2)
, patients in whom CE<70%, i.e. who had echocardiographic evidence of chronic ischaemia, had lower Troponin T levels at 48 and 72 h than those patients with preoperative values of CE>70%. The 72 h values remained significant (P=0.009) even when adjusted for multiple comparisons. Total postoperative troponin release was measured as the area under the curve when days 1, 2, and 3 were plotted. This was also significantly lower in the ischaemic group (median (SD) 10.1 µg/l h (13) vs 7.1 (4.2), P<0.02) (Table 2).
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Fig. 2. Venous Troponin T release in patients with asynchronous ventricular contraction (cycle efficiency (CE)<70%) and synchronous ventricular contraction (CE>70%). The bar represents median and 25/75th centile values whilst the limits enclose the entire range.
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3.3. Effects of chronic ischaemia on wall motion
Given the difference in Troponin T release in the two patient groups, we analysed the corresponding changes in regional wall dynamics (Table 3). Patients with preoperative asynchrony had lower resting values of peak power and regional myocardial work than those without and, furthermore, these indices all increased within 30 min of revascularisation. An example of significant postoperative improvement in a patient with preoperative asynchrony is shown in Fig. 3
In the non-ischaemic group, these values were unaltered after surgery.
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Fig. 3. An example of an asynchronous (‘ischaemic’) preoperative pressure-wall thickness loop (pre) which normalises within 30 min of revascularisation (post). Note also the increase in loop area postoperatively (representing increased effective work).
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3.4. Effects of a surgical ischaemic preconditioning protocol
The 21 patients undergoing two vessel bypass grafting were also analysed as a subgroup to examine the effect of the surgical preconditioning protocol separately. Troponin T release was similar at 24 and 48 h, but higher at 72 h in those undergoing the surgical preconditioning protocol (0.11 (0.09–0.16) vs 0.24 (0.11–0.36) ns), although postoperative regional wall dynamics were unaffected.
3.5. Determinants of troponin release
Due to the wide spread of ages and ischaemic times (the two main factors known to influence myocyte injury) multiple stepwise linear regression was undertaken. A Friedman test demonstrated no difference with respect to time over days 1, 2 and 3, therefore, postoperative troponin release was taken as the area under the curve of Troponin T release on days 1, 2 and 3. This measure was used in order to account for the biphasic release characteristics seen after coronary surgery [13,14,16,17]. The independent variables entered in the model for all 33 patients were cycle efficiency (%), ischaemic time (min), age (years) and surgical preconditioning (yes in 11 patients, no in the remainder). Univariate analysis (Table 4) demonstrated that ischaemic time and cycle efficiency, but not surgical preconditioning were significant determinants of postoperative Troponin T release. Although it had a similar correlation coefficient, age just failed to reach statistical significance. Troponin T release was greater; the longer the ischaemic time, the greater the age and the higher, i.e. the more synchronous, the preoperative contraction pattern.
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Table 4. Univariate determinants of postoperative Troponin T release (area under the curve of troponin release at days 1, 2 and 3)
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Stepwise multivariate analysis confirmed that ischaemic time and cycle efficiency were independent predictors of postoperative troponin release. Overall R squared was 0.40 with an adjusted R squared 0.33. Surgical ischaemic preconditioning was not an independent variable when analysed by multiple regression.
3.6. Influence of collateral supply
When average collateral score was correlated with troponin release no significant correlation was found (r=–0.27, P=0.36). There was no difference in mean collateral score between the ischaemic and non-ischaemic groups (ischaemic 1.4 (0.9), non-ischaemic 1.3 (1.0)).
3.7. Reproducibility
The coefficient of variability of the measurements for left ventricular dimensions and cycle efficiency, ranged between 4.8 and 8.4%. Myocardial power and work had a variability of 9.2 and 7.3%, respectively.
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4. Discussion
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In animals with normal coronary arteries, ischaemic preconditioning by short periods of complete arterial occlusion protects the myocardium from more prolonged episodes of regional and global ischaemia [5,18]. In humans, in the setting of acute myocardial infarction, preinfarct angina has been described as limiting the degree of myocardial necrosis by a similar mechanism [19]. The aim of this study, therefore, was to see if the presence of the naturally occurring chronic stable ischaemia, present in many patients preoperatively, could influence Troponin T release during the acute coronary occlusion necessary in beating heart surgery. In patients with preserved left ventricular function, age, ischaemic time and the presence of a surgical preconditioning protocol are all known to be important determinants of troponin release. We therefore designed our study to incorporate significant variability in the above three factors, in order that any effect of chronic ischaemia on troponin release could be compared with well documented determinants.
4.1. Determinants of Troponin T release
There were three significant independent determinants of troponin release. As expected, a longer duration of ischaemia and a higher age was associated with increased Troponin T release (although age just failed to reach significance in the regression model). The third independent determinant proved to be cycle efficiency, a sensitive marker of both acute and chronic ischaemia [6,7]. Postoperative Troponin T release (measured either at 48 and 72 h or as the total area under the curve for days 1, 2 and 3) was reduced in patients in whom preoperative cycle efficiency was low, i.e. in whom anterior wall motion was asynchronous. This implies that myocyte injury was lower rather than higher in patients demonstrating chronic preoperative ischaemia. Indeed, resting asynchrony proved as strong a negative determinant of myocyte injury as total ischaemic time proved a positive one. This relationship persisted even when the other major determinants of myocyte injury, age and ischaemic time, were allowed for, and was independent of collateral supply. Furthermore, local asynchrony was accompanied by reduced values of peak power and myocardial work, all of which rapidly normalised after coronary grafting.
By contrast, our results also showed that, in the patients with two vessel disease, a surgical protocol for ischaemic preconditioning did not give the protection seen in those with no spontaneously occurring preoperative ischaemia. Indeed in those undergoing the preconditioning protocol, the trend was for higher troponin levels. These results appear contradictory, especially as the protocol we used has been shown to be effective during the more substantial ischaemic insult of multivessel coronary grafting using cardiopulmonary bypass [9]. However, the classical experimental definition of ischaemic preconditioning is limitation of infarct size [5] and in our study the levels of Troponin T release, and therefore myocyte death, were low. Our results therefore suggest that uncomplicated beating heart surgery causes low levels of ischaemic damage for which classical ischaemic preconditioning is inappropriate.
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5. Limitations
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Measurements were made with the patient in a steady state, and neither mean arterial pressure nor left ventricular end diastolic pressure changed between the two time points. Any effect of loading conditions will therefore have been small. Troponin levels were similar between the ischaemic and non-ischaemic groups at 24 h, a time point which is known to carry prognostic importance. However, the cumulative release after surgery (as measured by the area under the curve) and the day 2 and 3 levels were all different. This may reflect a different pattern of release and may help to elucidate the underlying mechanisms. Our study was not designed to study the prognostic significance of the troponin values though we hope future studies may answer this. We assessed collateral supply from the angiograms, which may not provide a completely accurate representation of true collateral supply although it has been shown to predict major differences in the extent of local asynchrony after acute occlusion [7]. While collaterals may reduce the intensity of the ischaemia provoked by local arterial occlusion, their presence would not explain the protective effect of preoperative ischaemia. Finally, intracoronary shunts were not used. Since the end of this study, these have now become routine practice in our institution. However, the fact our study predates their use potentially makes it a better model of warm regional ischaemia.
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6. Conclusions
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Our results show that local asynchrony associated with depressed mechanical function present preoperatively, reduces myocyte damage during beating heart surgery. The rapid normalisation of these values with revascularisation strongly suggests that preoperative asynchrony is a marker of chronic local ischaemia. By contrast, this effect could not be induced by brief periods of acute vascular occlusion, suggesting a quite different mechanism from classical ischaemic preconditioning. The duration of reduced perfusion necessary to induce naturally occurring asynchrony seen clinically may be well outside that used in animal models and its intensity less, so that it is only seen in humans with chronic coronary artery disease. We hypothesise that it may be the result of the metabolic alterations occurring in response to the chronic diminution of arterial blood supply present preoperatively. Examining fundamental mechanisms underlying this naturally occurring form of myocardial protection may perhaps lead to more effective protocols or pharmacological treatments becoming available in the future.
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Acknowledgments
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GCW is supported by a British Heart Foundation Junior Research Fellowship.
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Footnotes
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1 GS Carr-White is a British Heart Foundation Junior Research Fellow. 
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Abstract
1. Introduction
