On-Pump, Beating-Heart Coronary Artery Operations in High-Risk Patients: An Acceptable Trade-off?

On-Pump, Beating-Heart Coronary Artery Operations in High-Risk Patients: An Acceptable Trade-off? Louis P. Perrault, MD, PhD, Philippe Menasché, MD, PhD, Jacqueline Peynet, MD, Bouchaib Faris, MD, Alain Bel, MD, Thierry de Chaumaray, MD, Claire Gatecel, MD, Bernard Touchot, MD, Gérard Bloch, MD, and Jean-Marie Moalic, PhD Department of Cardiovascular Surgery and INSERM U-127, Hôpital Lariboisière, Paris, France Background. Current cardioplegic techniques do not consistently avoid myocardial ischemic damage in highrisk patients undergoing coronary artery bypass grafting. Alternatively, revascularization without cardiopulmonary bypass is not always technically feasible. We investigated whether an intermediary approach based on maintenance of a beating heart with cardiopulmonary bypass support but without aortic cross-clamping might be an acceptable trade-off. Methods. Thirty-seven consecutive patients underwent coronary artery bypass grafting (with an average of two grafts per patient) in a pump-supported, non crossclamped beating heart. Inclusion criteria were poor left ventricular function (18 patients; mean ejection fraction, 0.25), evolving myocardial ischemia or infarction (11 patients, 5 of whom were in cardiogenic shock), and advanced age (3 patients; mean age 79.5 years) with comorbidities. Results were assessed primarily on the basis of clinical outcome. In addition, measurements of plasma levels of markers of myocardial damage (troponin I c ) and systemic inflammation (interleukin-6, interleukin-10, elastase) were done in 9 patients before and after bypass. In 6 patients, right atrial biopsy specimens were taken before and after bypass and processed by Northern blotting for the expression of messenger ribonucleic acid coding for the cardioprotective heat-shock protein 70. These biologic data were compared with those from control patients who underwent warm cardioplegic arrest within the same time span. Results. There was one cardiac-related death (2.7%), one Q-wave myocardial infarction, and no strokes. Four other deaths occurred from noncardiac causes, yielding an overall mortality rate of 13.5%. Limitation of myocardial injury was demonstrated by the minimal increase in postoperative troponin I c levels (3.3 1.0 g/l versus 6.6 1.5 g/l in controls; p < 0.05) and the finding that heat-shock protein 70 messenger ribonucleic acid levels (expressed as a percentage of an internal standard) were significantly increased after bypass compared with prebypass values (279% 80% versus 97% 21%; p < 0.05). In the control group (cardioplegia), end-arrest values of heat-shock protein 70 messenger ribonucleic acid were not significantly changed from baseline (148% 49% versus 91% 29%), a finding suggesting a defective adaptive response to surgical stress. Conversely, peak levels of inflammatory mediators were not significantly different between the two groups. The eight grafts to the left anterior descending coronary artery that were assessed angiographically, by transthoracic Doppler echocardiography, or both methods were patent with satisfactory anastomoses. Conclusions. In select high-risk patients, on-pump, beating-heart coronary artery bypass grafting may be an acceptable trade-off between conventional cardioplegia and off-pump operations. It is still associated with the potentially detrimental effects of cardiopulmonary bypass but eliminates intraoperative global myocardial ischemia. (Ann Thorac Surg 1997;64:1368 73) 1997 by The Society of Thoracic Surgeons Recently, minimally invasive coronary artery bypass grafting has been the subject of several studies, with emphasis usually put on the switch from conventional median sternotomy to minithoracotomy [1, 2] or even port access [3]. We believe, however, that the invasiveness of coronary artery operations is determined more by Accepted for publication June 3, 1997. Address reprint requests to Dr Menasché, Hôpital Lariboisière, 2 rue Ambroise Paré, Paris Cedex, France. myocardial ischemia incurred during the cross-clamping period and the inflammatory response to cardiopulmonary bypass (CPB) than by the site and type of incision. Ideally, these two issues are addressed by off-pump surgery, but this strategy, which is far from new [4], raises the very concerns that led to the development of CPB. An intermediary option is to continue to use CPB but to eliminate the ischemic component of invasiveness by avoiding aortic cross-clamping and keeping the heart beating throughout the operation. Here we report our experience with this technique in a select group of 37 1997 by The Society of Thoracic Surgeons 0003-4975/97/$17.00 Published by Elsevier Science Inc PII S0003-4975(97)00842-4

Ann Thorac Surg PERRAULT ET AL 1997;64:1368 73 BEATING-HEART CORONARY ARTERY OPERATIONS 1369 Table 1. Patient Data a Beating Heart Group (n 37) Variable Subgroup A (EF 0.30) (n 18) Subgroup B (Emergency) (n 11) Subgroup C (Age/Comorbidities) (n 8) Age (y) 64 12 69 12 80 5 Sex ratio (male/female) 17/1 7/4 8/0 Unstable angina 0 6 0 Preop IABP 6 8 0 Cardiogenic shock 0 5 0 LV ejection fraction 0.25 0.06 0.39 0.03 0.47 0.03 a Data are shown either as the mean the standard error of the mean or as number of patients. EF ejection fraction; IABP intraaortic balloon pump; LV left ventricular. high-risk patients deemed most likely to benefit from a reduction in perioperative myocardial ischemic injury. Material and Methods Thirty-seven patients were consecutively enrolled in this study. They were divided into three subgroups on the basis of the indications for on-pump, beating-heart coronary artery bypass: subgroup A, poor left ventricular function defined as a left ventricular ejection fraction of 0.30 or less; subgroup B, evolving myocardial ischemia or infarction at the time of operation; and subgroup C, advanced age with major comorbidities (Table 1). Eighteen patients, 17 men and 1 woman with a mean age of 64 years (range, 40 to 80 years), had poor left ventricular function (mean ejection fraction, 0.25). Six of them required intraaortic balloon pump support before the operation. Eleven patients underwent urgent or emergent coronary artery bypass grafting for evolving myocardial ischemia refractory to medical therapy, including intravenous administration of nitroglycerin. Five were in cardiogenic shock complicating an acute myocardial infarction. There were 7 men and 4 women with an average of 68 years (range, 41 to 85 years). Eight patients in this subgroup had insertion of an intraaortic balloon pump before the operation. The third subgroup comprised 8 elderly men (mean age, 79.5 years; range, 69 to 83 years) with major renal (4 patients) or neurologic comorbidities (2 patients). Distribution of coronary artery disease and operative data are presented in Table 2. In 31 patients, total CPB was established with a Duraflo II heparin-coated circuit (Baxter Healthcare Corp, Bentley Division, Irvine, CA) between the two individually cannulated venae cavae and the ascending aorta. A membrane oxygenator was used in all operations, and the left ventricle was consistently vented through the right superior pulmonary vein. In the 6 remaining patients (5 from subgroup A, 1 from subgroup B), left heart bypass was instituted between the left atrium and the ascending aorta using a similar heparin-coated tubing and a centrifugal pump (Bio-Medicus, Minneapolis, MN). In all patients, core temperature was allowed to drift, usually to 33 to 34 C, and ventilation was maintained throughout the operation. The target vessel was occluded proximally and distally using a 4-0 polytetrafluoroethylene suture passed twice beneath the artery and mattressed on a small piece of silicone tubing to prevent direct contact between the suture and the anterior coronary artery wall. In 13 patients, a bolus dose of 1 mg/kg of esmolol hydrochloride (Brevibloc; Gensia, Bracknell, UK) was used to slow the heart rate. The efficacy of this drug, however, has been inconsistent, and with increasing experience, the use of drugs intended to cause bradycardia has been discontinued. The first saphenous vein graft was anastomosed distally to the target coronary vessel and then to the aorta with the aid of a side-biting clamp after careful digital palpation of the aorta and with the pump off. When a second venous conduit had to be placed, its proximal end was sutured first to the aorta during the same period of partial occlusion, both to avoid repeated applications of the side-biting clamp and to allow for immediate myocardial revascularization on completion of the corresponding distal anastomosis. The left internal mammary artery left anterior descending coronary artery anastomosis was constructed last when the saphenous vein grafts were already functional. All distal anastomoses were performed with running sutures of 7-0 or 8-0 Prolene (Ethicon, Somerville, NJ). Each patient received Table 2. Summary of Operative Data Variable Beating Heart Group (n 37) Subgroup A Subgroup B Subgroup C No. of diseased vessels 3 0.1 2.7 0.1 2.6 0.2 No. of grafts 2.2 0.2 2.0 0.2 1.8 0.1 Target vessel LAD 14 13 7 LCx 8 4 5 RC 4 5 4 Esmolol 8 2 3 a Data are shown as the mean the standard error of the mean or as number of patients. LAD left anterior descending coronary artery; LCx left circumflex artery; RC right coronary artery.

1370 PERRAULT ET AL Ann Thorac Surg BEATING-HEART CORONARY ARTERY OPERATIONS 1997;64:1368 73 an average of two grafts (range, one to three) with the time of coronary occlusion ranging between 10 to 20 minutes. Complete data concerning the extent of revascularization are summarized in Table 2. No coronary arteries were left ungrafted because of technical difficulty. Vessels that were not bypassed either were occluded or were not of critical importance in patients in unstable condition. Results were assessed primarily on clinical outcome, which included mortality, Q-wave infarction, requirement of inotropic agents or an intraaortic balloon pump, occurrence of stroke, and time to extubation. The alveolar-arterial oxygen pressure gradient [P(A-a)O 2 ] was calculated at the time of anesthesia induction and on arrival in the intensive care unit with the following formula: P(A-a)O 2 PAo 2 PaO 2, where PAo 2 PiO 2 PaCO 2 /RQ (PiO 2 is the product of the inspired oxygen fraction and the dry barometric pressure [760 mm Hg 47 mm Hg], PaCO 2 is the partial pressure of arterial carbon dioxide, and RQ is the respiratory quotient [taken at 0.77]), and PaO 2 is the partial pressure of arterial oxygen [5]. Eight grafts to the left anterior descending coronary artery (seven mammary arteries, one vein) were controlled by angiography (six grafts; five in subgroup A, one in subgroup B) or transthoracic Doppler echocardiography (two grafts; one in subgroup B, one in subgroup C) within 1 week postoperatively. Further, in 9 randomly selected patients (5 from subgroup A, 2 from subgroup B, 2 from subgroup C), arterial blood samples were collected preoperatively and 4 hours after completion of CPB. Samples were processed for the determination of troponin I c, interleukin-6, interleukin-10, and elastase using enzyme-linked immunosorbent assays (troponin I c : Dade, Massy, France; interleukins 6 and 10: R & D Systems, Minneapolis, MN; elastase: Merck Diagnostica, Darmstadt, Germany). All postbypass values were corrected for hemodilution. In 6 patients (all from subgroup A), right atrial biopsy specimens were taken before and after bypass and processed by Northern blotting for the expression of messenger ribonucleic acid (mrna) coding for the cardioprotective heat-shock protein (HSP) 70, as previously described [6]. Data on troponin I c, inflammatory mediators, and HSP 70 mrna were compared with those obtained in control patients operated on during the same period with the use of continuous retrograde warm blood cardioplegia and a similar heparin-coated extracorporeal circuit. Results were compared using paired and unpaired Student s t tests, where appropriate. Statistical significance was set at the 0.05 level. Data are expressed as the mean the standard error of the mean. Results There was one cardiac-related death. A 71-year-old woman underwent emergent redo operation for unstable angina complicated by congestive heart failure requiring balloon pump support. Despite an uneventful triple bypass procedure, a low-output state persisted postoperatively and ultimately caused her death 14 days after the operation. There were four other deaths from noncardiac causes. Two patients died of multiorgan failure complicating preoperative cardiogenic shock. In both, myocardial function had recovered in the early postoperative period, and this allowed 1 to be successfully weaned from a left ventricular assist device after 11 days of support. A 75-year-old man with diffuse atherosclerotic disease died on the fourth postoperative day of massive gastric bleeding that caused irreversible hypotension before a laparotomy could be performed. At postmortem examination, the endarterectomized left anterior descending coronary artery and the internal mammary artery graft were patent. A 78-year-old man died suddenly on postoperative day 4 of a pulmonary embolism documented at postmortem examination. Thus, the overall operative mortality rate was 13.5% (5/37), but the cardiac-related mortality rate was only 2.7%.* One patient sustained a nonfatal Q-wave infarction. Postoperative inotropic support for more than 24 hours and an intraaortic balloon pump were required in 8 and 4 patients, respectively. No patient had a stroke. Twentyseven patients were extubated within 18 hours after operation, and the early postoperative alveolar-arterial oxygen pressure gradient (at an inspired oxygen fraction of 1.0) was not significantly different from the prebypass value (345 19 mm Hg and 332 22 mm Hg, respectively). Clinical outcomes were not different between patients having operation on full versus left heart bypass only. The eight left anterior descending coronary artery bypass grafts assessed postoperatively were patent with normal anastomoses and flows. Postoperative levels of troponin I c were twofold lower in the beating heart group compared with the cardioplegia group (3.3 1.0 g/l versus 6.6 1.5 g/l in 11 controls; p 0.05). Additional evidence for the superior myocardial protection afforded by the beating heart technique is based on the finding that in the beating heart group, postbypass values for HSP 70 mrna (expressed as a percentage of an internal standard) were significantly increased after bypass compared with prebypass values (279% 80% versus 97% 21%, p 0.05), whereas in 10 control patients undergoing continuous warm cardioplegia, end-arrest values of HSP 70 mrna were not significantly different from baseline (148% 49% versus 91% 29%). Conversely, there were no significant differences in the postbypass release of interleukin-6, interleukin-10, and elastase between the two groups (Table 3). Comment Despite the major advances in myocardial protection that have occurred over the last decade, postoperative adverse events related to intraoperative ischemia have not been completely eliminated. Even continuous warm * Since the manuscript was submitted, 6 additional patients have undergone an on-pump beating-heart operation with no deaths. This yields a cardiac-related mortality of 2.3% and an overall mortality rate of 11.6% (5/43).

Ann Thorac Surg PERRAULT ET AL 1997;64:1368 73 BEATING-HEART CORONARY ARTERY OPERATIONS 1371 Table 3. Comparison of Effects of Beating Heart Technique and Warm Blood Cardioplegia on Inflammatory Markers a Variable Beating Heart (n 9) Warm Blood Cardioplegia (n 11) Before CPB 4 Hours After CPB Before CPB 4 Hours After CPB Interleukin-6 (ng/l) 5.2 1.4 858.0 338.7 3.5 0.7 1,435.0 790.9 Interleukin-10 (ng/l) 3.4 0.6 54.0 12.5 3.4 0.4 65.3 20.7 Elastase ( g/l) 43 2 364 70 55 4 348 41 a Data are shown as the mean the standard error of the mean. CPB cardiopulmonary bypass. blood cardioplegia, which is expected to keep the heart in an aerobic environment, does not completely prevent some degree of postoperative stunning [7], possibly because the myocardial edema intrinsic to the diastolic state of the arrested heart can cause cardiac dysfunction [8]. Conversely, keeping the heart beating, even with reduced contractility such as under -blockade, is associated with less myocardial edema and better function [8]. The detrimental effects of aortic cross-clamping are probably inconsequential in the vast majority of patients but may precipitate hemodynamic failure in patients with already marginal left ventricular function. Theoretically, the ideal solution to this problem is myocardial revascularization without extracorporeal circulation. However, this approach raises its own concerns, as demonstrated by the sharp contrast between satisfactory clinical outcomes [9 12] and the low rates of long-term graft patency [13]. We acknowledge that, by virtue of the observational design of this study, the present data do not conclusively establish the superiority of the beating heart technique over any other method of myocardial protection; in fact, excellent clinical results have been reported in high-risk patients with the use of different strategies of cardioplegia [14, 15]. Nevertheless, low ejection fraction, evolving myocardial ischemia, and advanced age are all factors for increased morbidity and mortality after coronary artery bypass grafting [16], and this alone provides a sound rationale for the investigation of alternative surgical approaches in high-risk patients. For this reason, onpump, beating-heart bypass might constitute, in select patients, an interesting trade-off, as suggested by the results reported by Sweeney and Frazier [17] with the use of biventricular assist devices during coronary revascularization in a similar patient population. In keeping with these results, the present data show that maintenance of the heart in a beating state throughout the operation causes less damage than aortic crossclamping, even when blood cardioplegia is used in a continuous fashion. This conclusion is based on two specific findings a lower release of troponin I c, a highly cardiac specific marker of tissue damage [18], and a threefold increase in the postoperative myocardial content of mrna coding for HSP 70 compared with the preoperative value. This result reflects the preserved ability of the beating heart to display an appropriate adaptive response to surgical stress, whereas the arrested heart seems to have lost this capacity, as demonstrated by the fact that levels of HSP 70 mrna at the end of cross-clamping were unchanged from baseline in patients undergoing conventional warm cardioplegic arrest. This observation is consistent with that of McGrath and co-workers [19], who failed to document any change in myocardial levels of HSP 72 in patients protected with cardioplegia when undergoing various open heart operations. Several experimental studies have documented a close relationship between increased myocardial levels of HSPs and attenuation of stunning. Plumier and coauthors [20] and Marber and colleagues [21] have shown improved recovery after ischemia in mice overexpressing the gene for HSP. As ischemia seems to prevent the expression of HSPs [22], the present study documents at the molecular level, the effectiveness of the beating heart technique in ensuring adequate prevention against myocardial injury, thereby making this technique a major component of any minimally invasive procedure. In contrast to the measurements of markers of myocardial damage, those more specific for systemic inflammation were not significantly different between the beating heart technique and warm blood cardioplegia. Of the inflammatory mediators released during CPB, elastase, interleukin-6, and interleukin-10 were selected because they have been shown to be sensitive markers of neutrophil activation, proinflammatory cytokine production, and antiinflammatory cytokine production, respectively [23, 24]. From this standpoint, our results may look disappointing because blood levels of these mediators were not reduced in patients whose hearts were kept beating compared with those having cardioplegic arrest. Nevertheless, the ischemic and reperfused myocardium has been shown to be a major source of inflammatory mediators, in particular neutrophil chemotactic factors and cytokines [25, 26]. Thus, it is possible that we failed to capture this myocardium-specific production because of the timing and site of blood samples. Samples were taken 4 hours after bypass, as previous studies from our institution [27, 28] and others [24, 29] have shown that elastase and interleukin-6 levels peak around this time. This may have led us to miss the release of these mediators from the myocardium, a release that has recently been shown to occur early after aortic unclamping [26]. Also, because at this 4-hour point patients could not have placement of coronary sinus catheters, blood samples were collected from peripheral blood, which

1372 PERRAULT ET AL Ann Thorac Surg BEATING-HEART CORONARY ARTERY OPERATIONS 1997;64:1368 73 does not allow distinction between the myocardial component of elastase and cytokine production and that of systemic origin. There is no question that, regardless of their source, inflammatory mediators were still released in response to CPB. However, there is no conclusive evidence that this translated into clinically relevant postoperative adverse events, in particular in regard to pulmonary function and time to extubation, except for patients in preoperative cardiogenic shock in whom superimposed extracorporeal circulation most likely contributed to the worsening of organ dysfunction. Whether the magnitude of the response was mitigated by the use of heparin-coated circuits, as suggested by some studies [30], cannot be determined from our data. Four limitations of this study need to be addressed. First, one could argue that the comparison of various biologic markers between patients undergoing beatingheart operation and those protected by cardioplegia is flawed by the fact that the two patient populations were not case-matched. This is inherent to the study design, which implied the assignment of all patients meeting the inclusion criteria to the beating heart technique. Nevertheless, despite differences in preoperative clinical characteristics, prebypass values for troponin I c, inflammatory markers, and HSP 70 mrna were not significantly different between the two groups, which permits comparison of postbypass patterns. Second, molecular biologic determinations were made from tissue taken from the right atrium, not the left ventricle. This choice was dictated by obvious ethical considerations. It is clear that we cannot eliminate a spatially heterogeneous distribution of HSP expression [31] with, in particular, a weak expression in the area of regional ischemia possibly created by the vessel occlusion at the time of construction of the distal coronary anastomosis. Third, although we cannot rule out that vessel occlusion may have caused some regional ischemia, its true occurrence is questionable in view of the backflow of blood that consistently exited the distal end of the arteriotomy and that reflects the development of extensive collateralization in chronically ischemic hearts. Fourth, we recognize that complete validation of the technique presented here would require that all grafts be angiographically controlled after operation and followed up for a longer time. However, despite motion of the heart, the on-pump and well-decompressed heart allows the construction of distal coronary anastomoses, including posterior vessels, with an ease that should not compromise technical accuracy. This assumption tends to be supported by the satisfactory patency rates observed in those of our patients in whom left anterior descending coronary artery grafts were controlled postoperatively. In conclusion, we do not believe that the on-pump, beating heart technique is a panacea, but it may be a transitional step to off-pump coronary artery bypass grafting. In select high-risk patients who may poorly tolerate cardioplegic arrest and in situations where offpump surgical intervention is not technically feasible, myocardial revascularization on the pump-supported, non cross-clamped heart may be an acceptable alternative. In some cases, this approach can also be used for revascularizing only posterior vessels in patients whose more accessible coronary arteries are grafted concomitantly without extracorporeal circulation. Doctor Perrault is supported by the Clinician-Scientist program of the Medical Research Council of Canada. We acknowledge the help of Madame Roselyne Prioux in the preparation of the manuscript. References 1. Sani G, Benetti F, Mariani MA, Lisi G, Maccherini M, Toscano M. Arterial myocardial revascularization without cardiopulmonary bypass through a small thoracotomy. Eur J Cardio-thorac Surg 1996;10:699 701. 2. Calafiore AM, Di Giammarco G, Teodori G, et al. Left anterior descending coronary artery grafting via left anterior small thoracotomy without cardiopulmonary bypass. Ann Thorac Surg 1996;61:1658 65. 3. Stevens JH, Burdon TA, Siegel LC, et al. Port-access coronary artery bypass with cardioplegic arrest: acute and chronic canine studies. Ann Thorac Surg 1996;62:435 41. 4. 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Ann Thorac Surg PERRAULT ET AL 1997;64:1368 73 BEATING-HEART CORONARY ARTERY OPERATIONS 1373 18. Adams JE, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation 1993;88:750 63. 19. McGrath LB, Locke M, Cane M, Chen C, Ianuzzo CD. Heat shock protein (HSP 72) expression in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1995;109:370 6. 20. Plumier JCL, Ross BM, Currie RW, et al. Transgenic mice expressing the human heat shock protein 70 have improved post-ischemic myocardial recovery. J Clin Invest 1995;95: 1854 60. 21. Marber MS, Mestril R, Chi SH, Sayen MR, Yellon DM, Dillmann WH. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 1995; 95:1446 6. 22. Plumier JCL, Robertson HA, Currie RW. Differential accumulation of mrna for immediate early genes and heat shock genes in heart after ischaemic injury. J Mol Cell Cardiol 1996;28:1251 60. 23. Faymonville ME, Pincemail J, Duchateau J, et al. Myeloperoxidase and elastase as markers of leukocyte activation during cardiopulmonary bypass in humans. J Thorac Cardiovasc Surg 1991;102:309 17. 24. Steinberg JB, Kapelanski DP, Olson JD, Weiler JM, Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:1008 16. 25. Elgebaly SA, Hashmi FS, Houser SL, Allam ME, Doyle K. Cardiac-derived neutrophil chemotactic factors. Detection in coronary sinus effluents of patients undergoing myocardial revascularization. J Thorac Cardiovasc Surg 1992;103:952 9. 26. Wan S, DeSmet JM, Barvais L, Goldstein M, Vincent JL, LeClerc JL. Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1996;112:806 11. 27. Menasché P, Haydar S, Peynet J, et al. A potential mechanism of vasodilation after warm heart surgery. The temperature-dependent release of cytokines. J Thorac Cardiovasc Surg 1994;107:293 9. 28. Menasché P, Peynet J, Larivière J, et al. Does normothermia during cardiopulmonary bypass increase neutrophilendothelium interactions? Circulation 1994;90(Suppl 2): 275 9. 29. Wan S, Marchant A, DeSmet J, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996;111:469 77. 30. Weerwind PW, Maessen JG, van Tits LJH, et al. Influence of Duraflo II heparin-treated extracorporeal circuits on the systemic inflammatory response in patients having coronary bypass. J Thorac Cardiovasc Surg 1995;110:1633 41. 31. Heads RJ, Latchman DS, Yellon DM. Differential stress protein mrna expression during early ischaemic preconditioning in the rabbit heart and its relationship to adenosine receptor function. J Mol Cell Cardiol 1995;27:2133 48. Important Announcement for Authors We urge authors interested in submitting manuscripts to The Annals to read carefully the revised and updated Information for Authors sheet found in each issue of the journal. There are many important changes to be noted. For instance, we now require an original and three (instead of two) duplicate manuscripts, and four (instead of three) sets of illustrations. Because of the continuing escalation of production costs, greater attention must be given to the length of papers. Therefore guidelines for the suggested length of various articles are given both in the number of pages and the number of words. There are other significant changes as well. Failure to follow the instructions carefully may result in the manuscript being returned for further processing. 1997 by The Society of Thoracic Surgeons Ann Thorac Surg 1997;64:1373 0003-4975/97/$17.00 Published by Elsevier Science Inc PII S0003-4975(97)01163-6