Eur J Cardiothorac Surg 2001;20:1147-1151
© 2001 Elsevier Science NL
Off-pump coronary bypass surgery causes less immediate postoperative coronary endothelial dysfunction compared to on-pump coronary bypass surgery
Ulf Lockowandt,
Anders Franco-Cereceda
Department of Thoracic Surgery, Karolinska Hospital, 171 76 Stockholm, Sweden
Received 8 May 2001;
received in revised form 27 July 2001;
accepted 17 August 2001.
Corresponding author. Tel.: +46-8-51770000; fax: +46-8-322701
e-mail: ulf.lockowandt{at}ks.se
 |
Abstract
|
|---|
Objective: In this study a comparison of the vascular reactivity in the coronary circulation was investigated by injection of acetylcholine (ACh) and adenosine (ADO) in coronary bypass patients, operated on with or without the assistance of heart–lung machine. The patients operated on with heart–lung machine were further divided into subjects with stable or unstable angina pectoris. Methods: Nine patients with stable angina pectoris subjected to off-pump surgery (target arterial occlusion time of 11±0.5 min) and 18 patients subjected to on-pump surgery (nine patients with stable angina and nine patients with unstable angina; cross-clamp time of 43±3 and 32±2 min, respectively), received ACh (10 µg) and ADO (18 µg) given as bolus injections into a vein-graft anastomosed to a coronary vessel. The blood flow in the vein-graft (i.e. indirectly the flow in the targeted coronary circulation) and heamodynamics were observed. Results: In the off-pump group, ACh evoked an increase with +14±12% of control in coronary blood flow, while in the stable on-pump group ACh decreased the blood flow with -60±7% of baseline and in the unstable on-pump group the flow was decreased with -38±8% of baseline (P<0.001 between the stable on- and off-pump groups, no significant difference between the stable and unstable on-pump groups). ADO significantly increased the coronary blood flow in all three groups; with +81±14% in the off-pump patients; with +95±14% in the stable on-pump group and with +74±13% in the unstable on-pump group (P<0.01 compared to baseline for all three groups). Neither ACh nor ADO injection caused any changes in heamodynamics. Conclusions: The present study demonstrates that on-pump coronary bypass surgery appears to be more harmful to the coronary endothelium, in terms of ACh-induced vasoconstriction, compared to off-bypass pump surgery. Furthermore, there is no significant difference in direct smooth muscle vascular reactivity between off-pump and on-pump coronary bypass surgery. No apparent dissimilarities in endothelial dysfunction were observed in the stable and unstable on-pump groups suggesting other causes for differences in post-operative outcome for these patients.
Key Words: Coronary bypass surgery • Off-pump • Endothelium • Unstable angina
|
1. Introduction
|
|---|
Off-pump coronary artery bypass (OPCAB) is an increasingly widespread procedure. Most publications report that about 10% of patients admitted for coronary bypass procedures are suitable for off-pump surgery [1]. However, at some centres 70% of the cases of coronary bypass grafting (CABG) are performed without cardiopulmonary bypass (CPB) [2]. It has been hypothesised that elimination of CPB for coronary artery bypass surgery has the potential of reducing postoperative bleeding, cerebral complications, inflammatory response, peri-operative infarction and arrhythmias. A great number of papers regarding these parameters have been published [3]. Nevertheless, very little is known about the effect of the off-pump technique on the integrity and function of the endothelium of coronary arteries. Clinical and experimental studies have demonstrated that brief ischeamia and reperfusion induce a long-lasting impairment of endothelial function, with important clinical implications in terms of development of stenosis and coronary vasospasm [4,5].
In contrast to stable angina pectoris, unstable angina is associated with a higher early mortality, as well as a higher peri-operative myocardial infarction rate in unstable than stable patients [6]. It has been suggested that the difference in mortality could be caused by a persistent plaque instability after an acute rupture in unstable angina [7,8] and/or an increased coagulation system activity [9]. The role of the endothelium in the post-operative course has not been thoroughly investigated in these patients.
We have studied the vascular reactivity to the endothelium-dependent vasodilatation (acetylcholine; ACh) and the endothelium-independent vasodilatation (adenosine; ADO) in patients subjected to bypass surgery. The primary aim was to evaluate the effect of the off-pump technique on the immediate post-operative coronary endothelial function. In addition, we have investigated the smooth muscle and endothelial function in the coronary circulation in patients with unstable angina in relation to that of patients with stable angina.
|
2. Material and methods
|
|---|
This study was approved by the Local Ethical Committee of the Karolinska Hospital. Nine consecutive patients with stable angina pectoris undergoing coronary bypass surgery without heart–lung machine, and 18 consecutive patients with stable (nine patients) or unstable (nine patients) angina pectoris undergoing coronary bypass surgery with heart–lung machine, gave their informed consent to the investigation. The unstable patients were all in Braunwald class IIIB, i.e. angina at rest within 48 h preceding the operation. The operations were all performed by one single surgeon. Patients' characteristics are listed in Table 1.
The OPCAB patients were subjected to a midline sternotomy, fully heparinized (300 U/kg), and cannulated in the aorta and the right atrium, and subsequently connected to the heart–lung machine, as required by the Ethical Committee. The heart–lung machine was kept stand-by throughout the grafting and the injections of the vasoactive substances. The left internal mammary artery was harvested for anastomosis to the left anterior descending artery (LAD). Additional grafts were performed using the saphenous vein. An Ethiloop 1.1 mm (Ethicon, Johnsson and Johnsson, Sommerville, NJ, USA) was passed around the LAD proximal and/or just distal to the anastomotic site. There was no tightening of the snares to achieve ischeamic preconditioning. The anastomotic site was stabilised using an Octopus 3 (Medtronic Inc., Minneapolis, MN, USA). The anastomosis was then constructed using a 7-0 Prolene suture. The mean occlusion time of the arteries studied was 11±0.5 min.
The on-pump patients (stable and unstable) were operated on as routine cases with the use of CPB, aortic cross-clamp and ante- and retrograde blood cardioplegia. CPB was initiated using a centrifugal pump (BP 80, Biomedicus Biomed, Houston, TX, USA) and a membrane oxygenator (Affinity, Medtronic Inc, Minneapolis MN, USA) primed with Ringer's acetate solution. During CPB the temperature was allowed to drift to 34°C. Flow was kept around 4.7 l/min and mean arterial pressure (MAP) at about 75 mmHg. The cardioplegic solution was mixed 1:4 with blood and delivered at a temperature of 6°C. Content of cardioplegia is listed in Table 2. The patients were not decannulated until the injections were terminated, as required by the Ethical Committee. The mean cross-clamp for the stable group was 43±3 min and for the unstable group 32±2 min. Mean by-pass duration was 82±4 and 62±4 min for the stable and unstable group, respectively.
The injections were administered dissolved in 1 ml of 0.9% NaCl using a fine needle (/=0.4 mm) into a vein-graft anastomosed to either a diagonal branch of the LAD or a marginal branch of the circumflex artery, after completion of grafting with the patients off-pump but still cannulated and connected to the heart–lung machine. First ACh (10 µg) was given followed 10 min later by ADO (18 µg). Both substances were administered as bolus injections. The doses used were chosen based on earlier experimental studies [4,10]. There were no complications correlated to the injections recorded, and vehicle alone did not result in any changes in blood flow (n=4).
Blood flow was monitored using an ultrasonic flow probe PA 100021 (CardioMed AS, Oslo, Norway) placed around the vein-graft just proximal to the site of administration of substances, connected to a CM 1000 blood flow meter (CardioMed AS, Oslo, Norway). The flow probe consists of piezo-ceramic crystals. A reflector is placed on the opposite side of the crystal assembly. The time from transmit to receive is measured in both upstream and downstream directions. It is then subtracted, and the difference is proportional to the volumed flow through the vessel. The flow measurements are displayed on a monitor as pulsatile and mean curves, mean value is also numerically displayed. In our set-up the flow probe was positioned around the vein-graft prior to injections of the vasoactive substances and flow was subsequently registered continuously before, during and 10 min following the injections. Baseline and maximum deviation from baseline were registered. Heamodynamic parameters, including MAP, mean pulmonary artery pressure (MPAP) and ST segment deviation were continuously recorded. All patients were monitored with transesophageal echocardiogram throughout the operation.
2.1. Statistical analysis
Heamodynamics and blood flow were statistically analyzed by ordinary or repeated analysis of variance (ANOVA) with Student's t-test for paired and unpaired samples (INSTAT software, version 2.01; GraphPad, CA, USA): a P-value <0.05 was considered significant. Values are given as mean±SEM.
|
3. Results
|
|---|
3.1. Blood flow
In the off-pump group, ACh (Fig. 1
) evoked a small increase from 32.9±5.1 to 36.6±6.6 ml/min (+14±12% of baseline) in coronary blood flow, while in the stable on-pump group ACh caused the decrease in blood flow from 37.3±4.8 to 17.0±4.1 ml/min (-60±7% of baseline, P<0.001) and in the unstable on-pump group the flow decreased from 39.7±5.5 to 23.4±3.6 ml/min (-38±8% of baseline, P<0.01; P<0.001 between the stable on-pump and off-pump groups, no significant difference between the stable and unstable on-pump groups).
View larger version (16K):
[in this window]
[in a new window]
|
Fig. 1. Coronary blood flow as measured as vein-graft flow following injection of ACh (10 µg). Values are given as means±SEM and expressed as a percentage of baseline flow. **, P<0.01, ***, P<0.001, compared to off-pump group, Student's t-test for unpaired samples.
|
|
ADO (Fig. 2
) significantly increased the coronary blood flow in all three groups; from 30.7±4.9 to 55.3±10.4 ml/min (+81±14% of baseline) in the off-pump patients; from 36.4±14.4 to 70.1±10.9 ml/min (+95±4% of baseline) in the stable on-pump group and from 34.6±25.7 to 58.4±9.8 ml/min (+74±13% of baseline) in the unstable on-pump group (no statistically significant difference between the groups, but P<0.01 compared to baseline for all three groups). The coronary flow reserve, defined as the ratio of peak flow (measured after ADO injection) to baseline flow was calculated for every patient, the mean was 1.8±0.2, 1.9±0.1 and 1.7±0.1 in the off-pump group, the stable on-pump group and the unstable on-pump group, respectively.
View larger version (14K):
[in this window]
[in a new window]
|
Fig. 2. Coronary blood flow as measured as vein-graft flow following injection of ADO (18 µg). Values are given as means±SEM and expressed as a percentage of basline flow. **, P<0.01, compared to baseline, Student's t-test for paired samples.
|
|
3.2. Heamodynamics
The baseline MAP, MPAP and HR were similar in all three groups. (MAP, 70±2, 64±3, 71±2 mmHg; MPAP, 19±2, 17±1, 19±1 mmHg and HR, 70±4, 66±4, 77±4 bpm for the off-pump, stable and unstable group, respectively.) No effects on MAP, MPAP or HR were observed by the ACh and ADO injections. Furthermore, no electrocardiographic (ECG) changes or left ventricle mobility changes, as recorded by echocardiography, were registered in connection to any of the injections.
|
4. Discussion
|
|---|
In this study we have demonstrated that on-pump CABG results in a more pronounced endothelial dysfunction in the coronary arteries, as shown by a greater impairment of the vasodilator response to ACh, compared to off-pump CABG, while no difference in smooth muscle reactivity (i.e. the vasodilator response to ADO) could be observed between off- and on-pump surgery. Furthermore, when comparing patients with stable and unstable angina operated on with heart–lung machine, we did not find any differences in endothelial or vascular smooth muscle function.
It is known that the function and integrity of the endothelium is of importance for long-term results following CABG. Indeed, part of the superior patency rate for arterial grafts compared to vein-grafts, seems to be related to maintained endothelial function with production of vasodilator substances [11]. It is also acknowledged that several factors associated with coronary bypass surgery, such as degree of atherosclerosis, pre-operative high blood pressure and the operation per se, influence the condition of the endothelium [12–14]. The objective for the increase of the off-pump technique in CABG has been a belief in less post-operative complications. However, to what extent this operative technique is relevant for sustained endothelial function is not known.
The results following coronary bypass surgery of patients with unstable angina are less favourable compared to those with stable angina. There are several possible causes for this, such as a more vulnerable myocardium, plaque instability or changes in the coagulation system [15,16]. It seems plausible that the impaired blood flow in the coronary vessel could influence the endothelium and this in turn could have an impact on the post-operative outcome, although this has to our knowledge not been studied.
We found a clear-cut impairment in coronary blood flow following on-pump surgery and injection of ACh, indicating endothelial dysfunction. In the off-pump group there was no impairment of the flow following injection of ACh, but rather a tendency to vasodilatation. However, it should be stressed that the responses in the on-pump group as well as the off-pump group were abnormal when compared to the substantial dilatation that could be expected from healthy coronary arteries subjected to ACh [17]. The endothelium is thus impaired in both groups, although more severely so in the on-pump group. Our patients all have several conditions, which are known to depress dilator response to ACh, such as hypertension, hypercholesteroleamia, history of smoking, diabetes and medication, which did not differ between the groups. The added insult to the endothelium following coronary bypass surgery is in our study significantly greater when a heart–lung machine and cardiolplegia are used, compared to the off-pump technique.
To what extent the different elements of the CPB, i.e. cardioplegia, reperfusion, priming, blood flow or MAP, could be expected to alter the ACh reaction of the endothelium remains to be established.
There were no differences between patients with unstable and stable angina pectoris in vascular reactivity following injection of ACh immediately after on-pump CABG, indicating a similar degree of endothelial dysfunction in both groups of patients. This suggests that the integrity of the coronary endothelium following CABG does not play a significant role in the difference in outcome [6] between patients with stable and unstable angina pectoris.
In contrast to the response to ACh, there was an apparent and consistent vasodilator response to ADO in all three groups of patients, suggesting well functioning smooth muscle vascular cells, regardless if the patients were subjected to on- or off-pump surgery or if the patients were suffering from stable or unstable angina pectoris.
In conclusion, the integrity of the endothelium does not seem to influence the difference in outcome between patients with stable and unstable angina following on-pump CABG. Furthermore, CABG performed on-pump appears to be more harmful to the endothelium of the coronaries compared to surgery performed off-pump. To what extent a functional endothelium has a favourable influence on the post-operative course and outcome remains to be established.
|
Acknowledgments
|
|---|
Supported by grants from the Swedish Heart and Lung Foundation, the Wallenberg Foundation and funds from the Karolinska Institutet.
|
References
|
|---|
-
Pfister A.J. Coronary artery bypass without cardio-pulmonary bypass. Ann Thorac Surg 1999;67:1525.[Free Full Text]
-
Contini M., Iaco A., Iovini T., Teodori G., Di Giammarco G., Mazzei V., Commodo M., Calafiore A.M. Current results in off pump surgery. Eur J Cardiovasc Surg 1999;16(Suppl 1):69-72.
-
Svennevig J. Off-pump vs On-pump Surgery, a review. Scand Cardiovasc J 2000;34:7-11.[Medline]
-
Lockowandt U., Liska J., Franco-Cereceda A. Short ischemia causes endothelial dysfunction in porcine coronary vessels in an in vivo model. Ann Thorac Surg 2001;71:265-269.[Abstract/Free Full Text]
-
Sellke F.W., Boyle E.M., Verrier E.D. Endothelial cell injury in cardiovascular surgery: the pathophysiology of vasomotor dysfunction. Ann Thorac Surg 1996;62:1222-1228.[Abstract/Free Full Text]
-
Lougaie Y.A., Jamart J., Buche M., Eucher P.M., Schoervaerdts D., Collard E., Gonzalez M., Marchandise B., Scoiervaerdts J.C. Operation for unstable angina pectoris: factors influencing adverse in-hospital outcome. Ann Thorac Surg 1995;59:1141-1149.[Abstract/Free Full Text]
-
Merlini P.A., Bauer K.A., Oltrona L., Ardissino D., Cattaneo M., Belli C., Mannucci P.M., Rosenberg R.D. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994;90:61-68.[Abstract/Free Full Text]
-
FRISC II.Investigators. Long-term low-molecular-mass heparin in unstable coronary artery disease: prospective randomised multicenter study. Lancet 1999;354:701-707.[Medline]
-
Fuster V., Lewis A. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Conner Memorial lecture. Circulation 1994;90:2126-2146.[Abstract/Free Full Text]
-
Egashira K., Inou T., Hirooka Y., Yamada A., Maruoka Y., Kai H., Sugimachi M., Suzuki S., Takeshita A. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993;91:29-37.
-
Holm P., Franco-Cereceda A. Tissue concentrations of endothelins and functional effects of endothelin-receptor activation in human arteries and veins. J Thorac Cardiovasc Surg 1996;112:264-272.[Abstract/Free Full Text]
-
Lockowandt U., Öwall A., Franco-Cereceda A. Myocardial outflow of prostacyclin in relation to metabolic stress during off-pump coronary artery bypass grafting. Ann Thorac Surg 2000;70:206-211.[Abstract/Free Full Text]
-
Vita J.A., Treasure C.B., Nabel E.G., McLenachan J.M., Fish R.D., Yeung A.C., Vekshtein V.I., Selwyn A.P., Ganz P. Coronary vasomotor response to acetylcholine relates to risk factors or coronary artery disease. Circulation 1990;81:491-497.[Abstract/Free Full Text]
-
Ludmer P.L., Selwyn A.P., Shook T.L., Wayne R.R., Mudge G.H., Alexander R.W., Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315(17):1046-1051.[Abstract]
-
Fremes S.E., Goldman B.S., Christakis G.T., Ivanov J., Weisel R.D., Salerno T.A., David T.E. Current risk of coronary bypass for unstable angina. Eur J Cardiothorac Surg 1991;5:235-242.[Abstract]
-
Stuart R.S., Baumgartner W.A., Soule L., Borkon A.M., Gardner T.J., Watkins T., Jr, Reitz B.A. Predictors of operative mortality in patients with unstable postinfarction angina. Circulation 1988;78:I163-I165.
-
Hodgson J.M., Marshall J.J. Direct vasoconstriction and endothelium-dependent vasodilation. Mechanisms of acetylcholine effects on coronary flow and arterial diameter in patients with nonstenotic coronary arteries. Circulation 1989;79(5):1043-1051.[Abstract/Free Full Text]
Top
Abstract
1. Introduction
