Snaring of the Target Vessel in Less Invasive Bypass Operations Does Not Cause Endothelial

Snaring of the Target Vessel in Less Invasive Bypass Operations Does Not Cause Endothelial Dysfunction Louis P. Perrault, MD, Philippe Menasché, MD, PhD, Jean-Pierre Bidouard, PhD, Christine Jacquemin, Nicole Villeneuve, PhD, Jean-Paul Vilaine, MD, and Paul M. Vanhoutte, MD, PhD Cardiovascular Division, Institut de Recherches Servier, Suresnes; and Department of Cardiovascular Surgery, Hôpital Lariboisière, Paris, France Background. Minimally invasive coronary artery bypass grafting aims to achieve less patient discomfort and a more rapid return to active life. Most approaches have used maintenance of the beating heart and control of the target coronary vessel by different hemostatic devices. The purpose of this study was to assess the effects of commonly used coronary artery snares and of the occlusion of the coronary vessel necessary for minimally invasive coronary artery operations on coronary endothelial function. Methods. Coronary artery bypass grafting with an internal mammary artery to left anterior descending artery anastomosis was performed in a porcine model with a 30-minute period of ischemia and a subsequent 30-minute period of reperfusion, using snares on either side of the anastomotic site to achieve hemostasis of the operative field. Endothelium-dependent relaxation to serotonin was studied in conventional organ chamber experiments with rings taken from the left anterior descending artery at the proximal snare site, the anastomotic site in the segment that underwent the ischemiareperfusion cycle, the distal snare site, and at a control segment. Responses to potassium chloride and bradykinin were also compared. Results. There were no significant differences in endothelium-dependent relaxation values among the four sites studied. Conclusions. These results confirm that snaring of the coronary artery for achieving hemostasis at the anastomotic site when performing coronary artery bypass grafting on the beating heart does not cause endothelial dysfunction. (Ann Thorac Surg 1997;63:751 5) 1997 by The Society of Thoracic Surgeons Coronary artery bypass grafting (CABG) can be performed with the use of minimally invasive techniques both with and without bypass [1, 2]. Because most of these techniques avoid cross-clamping of the aorta and delivery of cardioplegic solutions, they are performed on the beating heart. However, manipulation of the target coronary artery vessel is necessary to achieve a clean surgical field for performance of a satisfactory anastomosis. Operative control [3] and ischemia-reperfusion [4] can lead to local coronary endothelial dysfunction. Such dysfunction may favor the occurrence of acute vasospasm, leading to hypoperfusion and the development of chronic intimal hyperplasia and atherosclerosis. The present experiments were designed to assess the effects of the looping snares commonly used for minimally invasive CABG on the endothelial function of target coronary arteries. Accepted for publication Oct 18, 1996. Address reprint requests to Dr Vanhoutte, Institut de Recherches Internationales Servier, 6 place des Pléiades, 92415, Courbevoie, France. Material and Methods Surgical Technique Large White swine (n 5) of either sex, aged 12 1 weeks and weighing 29.2 3 kg, were used in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication no. 85-23, revised 1985). After premedication with a mixture of tiletamine and zolazepam (15 mg/kg; injected intramuscularly), ventilatory support was established using a tracheostomy, intubation, and connection to a respirator (Mark 8; Bird Co, Palm Springs, CA). Oxygen supplementation was given to maintain an arterial oxygen saturation of 95%. Venous access for volume replacement with Ringer s lactate was obtained by cannulating the internal jugular vein. A catheter was placed in the left internal carotid artery for blood pressure monitoring and arterial gas analysis (ABL 300 Radiometer; Tacusel, Neuilly Plaisance, France). Anesthesia was maintained with sodium pentobarbital (8 mg kg 1 h 1 ; intravenous perfusion). After a median sternotomy, the pedicle of the left internal mammary artery was harvested in a standard fashion. After injection of heparin (300 U/kg), the graft was prepared for anastomosis. The bradycardic agent 1997 by The Society of Thoracic Surgeons 0003-4975/97/$17.00 Published by Elsevier Science Inc PII S0003-4975(96)01118-6

752 PERRAULT ET AL Ann Thorac Surg ENDOTHELIAL FUNCTION AFTER CABG 1997;63:751 5 had evidence of localized ischemia during the coronary occlusion, which subsequently improved during reperfusion. Electrocardiographic monitoring showed an increase in ST segment during the occlusion, 80% recovery of the changes at 12 1 minutes, and return to baseline at 24 4 minutes. There was no bleeding at the sites of passage of the Gore-Tex suture after reperfusion. Fig 1. Definition of the four segments of the left anterior descending coronary artery studied in the experimental protocol. (LAD left anterior descending artery; LCX left circumflex artery.) S16257 (0.5 mg/kg), which slows the rate of spontaneous firing in the isolated sinoatrial node by a reduction in the diastolic depolarization of the cells [5], was administered by bolus injection over 1 minute. The midportion of the left anterior descending artery distal to the first diagonal branch was then dissected and prepared for anastomosis. Injection of S16257 decreased the mean heart rate from 120 beats/min to a mean of 60 beats/min. In 1 swine, the bradycardic agent had no effect because of atrial fibrillation. The mean arterial pressure before anesthesia in swine is 85 2 mm Hg, and it was 73 3 mm Hg after anesthesia. The blood pressure after injecting the bradycardic drug was 70 4mmHg(p not significant). A snare was placed proximal to the anastomotic site using a 4-0 Gore-Tex suture with a 24-mm half-circle needle (W.L. Gore, Flagstaff, AZ). A double loop was passed under the coronary artery and buttressed with a 1-cm piece of silicone tubing. The same maneuver was performed distal to the anastomotic site. The distance between the snares varied between 2.5 and 3 cm. After snaring down of the sutures with sufficient tension to ensure a clean operative field, a 4-mm arteriotomy was performed. Then, a standard end to side left internal mammary artery to left anterior descending artery (average diameter 1.5 mm) anastomosis was performed using a running suture of 6-0 polypropylene. After a 30-minute period of coronary occlusion to mimic a worse than average clinical situation, the coronary artery was reperfused by release of the proximal and distal coronary snares and unclamping of the internal mammary artery for a 30-minute period (Fig 1). Defibrillation with 20 J energy was performed in all animals during the coronary occlusion period (mean 1.2 1.1 applications) and during the reperfusion period (3.2 1.7 applications). All hearts Endothelial Function After the ischemia-reperfusion period, the hearts were removed rapidly and placed in a modified Krebsbicarbonate solution (composition in mmol/l: NaCl, 118.3; KCl, 4.7; MgSO 4, 1.2; KH 2 PO 4, 1.2; glucose, 11.1; CaCl 2, 2.5; NaHCO 3, 25; and calcium ethylenediamine tetraacetic acid, 0.026; control solution). Oxygenation was ensured using a carbogen mixture (95% O 2 and 5% CO 2 ). The left anterior coronary artery was dissected free from the myocardium and epicardial tissue and was divided in rings 4 mm in width. Four different segments of the left anterior descending coronary artery were studied: the proximal unmanipulated left anterior descending artery that served as control (two rings), the site of the proximal snare application (two rings), the segment of the artery where the anastomosis was performed and that was submitted to ischemia and reperfusion (1 ring proximal and 1 ring distal to the anastomosis), and the site of the distal snare application (two rings). The endothelial function of the different rings was studied in organ chambers filled with control solution (20 ml). The rings were suspended between two metal stirrups, one of which was connected to an isometric force transducer and to an amplifier. Data were collected with a pen recorder (2400S; Gould, Ballainvilliers, France). Responses to potassium chloride, serotonin, and bradykinin were compared. All studies were performed in the presence of indomethacin (10 5 mol/l; to exclude the production of endogenous prostanoids), propranolol (10 7 mol/l; to prevent the activation of -adrenergic receptors), and ketanserin (10 6 mol/l; to block serotonin receptors on the coronary arterial smooth muscle). Each preparation was stretched to the optimal point of its active length-tension curve (usually 4 g), as determined by measuring the contraction to potassium chloride (30 mmol/l) at different levels of stretch, and then was allowed to stabilize for 90 minutes. Then, the maximal contraction was determined with potassium chloride (60 mmol/l). After washing and a further 30-minute equilibration period, prostaglandin F 2 (range, 2 10 6 to 10 5 mol/l) was added to achieve a contraction averaging 50% of the maximal contraction to KCl. Ketanserin was added 40 minutes before the addition of serotonin (10 9 to 10 5 mol/l). When the relaxation to serotonin did not achieve 100% of the contraction to prostaglandin F 2, bradykinin 10 8 mol/l was then added. Drugs All solutions were prepared daily. Prostaglandin F 2, 5-hydroxytryptamine creatinine sulfate (serotonin), ketanserin, bradykinin, indomethacin, and propranolol were purchased from Sigma Chemical Co (St.-Quentin

Ann Thorac Surg PERRAULT ET AL 1997;63:751 5 ENDOTHELIAL FUNCTION AFTER CABG 753 Table 1. Vascular Reactivity Data of the Four Experimental Groups a Variable Control Proximal Snare Ischemia-Reperfusion Distal Snare KCl 60 mmol/l (g) 8.9 3.6 7.9 2.5 6.3 2.1 7.1 2.5 PGF 2 (% contraction KCl) 51 9.8 54 9.7 49 9 50 11 EC 50 serotonin (mol/l) 3.24 10 7 4.11 10 7 1.57 10 7 4.56 10 7 Relaxation to bradykinin 10 8 mol/l (%) 100 0 100 0 100 0 100 0 a Data are expressed as mean standard error of the mean. EC 50 effective concentration of serotonin for obtaining 50% of relaxation to a prostaglandin F 2 contraction; PG prostaglandin. Falavier, France). The S16257 was synthesized at the Servier Research Institute (Suresnes, France). Statistical Analysis Relaxation was expressed as a percentage of contraction to prostaglandin F 2 for each group and is presented as mean standard error of the mean; n refers to the number of animals studied. One-factor analysis of variance was used for comparison of contractions to potassium chloride and prostaglandin F 2. Two-factor analysis of variance was used to compare dose-relaxation curves. Linear regression with repetition was performed for estimation of median effective concentration (EC 50 ) values. Values of p less than 0.05 were considered statistically significant. Results There were no statistically significant differences in the amplitudes of contractions to potassium and prostaglandin F 2 among all segments of the left anterior descending coronary artery, namely at the site of proximal snare application, the anastomotic site that incurred ischemia and reperfusion, the distal snare application site, and the control segment (Table 1). There were no statistically significant differences between maximal relaxation and the EC 50 to serotonin among the four groups (Fig 2). Relaxation to serotonin did not reach 100% of the contraction to prostaglandin F 2 in 9 of 10 control rings (90%), 6 of 10 proximal snare rings (60%), 8 of 9 ischemiareperfusion rings (88%), and in 6 of 10 distal snare rings (60%). The further addition of bradykinin in those rings achieved 100% relaxation in all cases. The EC 50 values were not significantly different between all four experimental groups. after laparoscopic cholecystectomy or chest wall tumor implantation after thoracoscopic resection of lung cancer [7, 8]. Enthusiasm has increased recently for the extension of these minimally invasive approaches to coronary artery revascularization in the hope of minimizing patient discomfort and shortening hospital stay, leading to an accelerated return to active life. The definition of what constitutes a minimally invasive approach is still blurry and includes the following: left anterior small thoracotomy with performance of internal mammary to coronary artery anastomosis off pump on the beating heart after administration of bradycardic agents [1, 2], the same procedure with harvest of the internal mammary artery graft through videothoracoscopic techniques, port access CABG procedures performed on bypass with endoluminal aortic clamping [9], and on bypass coronary revascularization on the arrested heart but without crossclamping [10]. Other techniques may be used to try to lessen the ischemic insult on the heart or the inflammatory response caused by cardiopulmonary bypass. An intraluminal shunt may be used, with the attendant concern for the potential endothelial cell denudation Comment Minimally invasive approaches have forever changed the face of general surgery and thoracic surgery practice using videoscopic equipment. Although the benefits of these approaches are not clear for all procedures, some, such as laparoscopic cholecystectomy, have become the technique of choice [6]. However, the capability of these techniques to reduce the invasiveness of conventional surgical procedures can occasionally be offset by specific complications, such as an increase in bile duct injury Fig 2. Cumulative concentration-relaxation curves to serotonin in rings of porcine left anterior descending coronary arteries with endothelium submitted to proximal snaring (n 5, squares), the anastomotic site submitted to 30 minutes of ischemia and 30 minutes of reperfusion (n 5, triangles), distal snaring (n 5, diamonds), and control (n 5, circles). Responses are given as a percentage of relaxation to the contraction induced by prostaglandin F 2 (PGF 2 ). Results are presented as mean standard error of the mean. (5-HT 5-hydroxytryptamine.)

754 PERRAULT ET AL Ann Thorac Surg ENDOTHELIAL FUNCTION AFTER CABG 1997;63:751 5 associated with any endoluminal manipulation [11]; left heart bypass may be useful to optimize the operating conditions [12]; or the revascularization may be performed through a standard sternotomy or ministernotomy without bypass [13, 14]. The place of each of these techniques will, one hopes, be clarified as the method for minimizing the invasiveness of CABG is more precisely identified. Our current opinion is that it is far more important to avoid myocardial ischemia associated with aortic cross-clamping and to limit the inflammatory response to cardiopulmonary bypass than to switch from sternotomy to thoracotomy. One way of avoiding ischemia is clearly to keep the heart beating, without cross-clamping the aorta. This in turn necessitates manipulation of the target coronary vessel and the use of hemostatic techniques to achieve a dry operative field, and a period of ischemia-reperfusion of the coronary segment on which the anastomosis is performed. Endothelial cells play a key role in the regulation of vascular homeostasis [15, 16]. Internal mammary artery clamping with commercially available clamps may injure the vascular endothelium, with resulting denudation of the endothelial cell coverage and decreased endothelium-dependent relaxation [17]. Similar vascular injury can occur through direct application of bulldog clamps or gas jet insufflation of the operative field [3] used during continuous blood cardioplegia. Likewise, concerns have been expressed over the occurrence of coronary arterial lesions at the site of encircling snares during off-pump bypass grafting operations [18]. Loss of endothelial cell coverage may be important clinically because regenerated endothelium presents a selective dysfunction with decreased endothelium-dependent relaxation mediated by pertussis toxin sensitive G-proteins. These alterations may accelerate the occurrence of vasospasm and atherosclerosis [19, 20]. Ischemiareperfusion of coronary arteries has also been implicated in a selective endothelial dysfunction involving G- protein mediated relaxation [4, 21, 22]. The current study shows that the hemostatic technique involving snaring of the proximal and distal left anterior descending coronary artery with double looping of a Gore-Tex suture over a silicone tubing, with sufficient tension to achieve a clear operative field, does not cause endothelial dysfunction. The present data also demonstrate that the coronary artery segment undergoing a 30-minute period of occlusion and 30 minutes of reperfusion does not exhibit decreased endothelium-dependent relaxation compared with a control coronary artery segment. Longer periods of ischemia (60 minutes) followed by reperfusion may lead to acute endothelial dysfunction [21 23]. As regards the acute impact on endothelial function per se in healthy blood vessels, the present results validate the safety of encircling snares on the beating heart for minimally invasive CABG. Obviously, caution must be used when extrapolating this conclusion to atherosclerotic vessels, which may already demonstrate endothelial dysfunction and may have a lesser tolerance to both operative manipulation and ischemia-reperfusion [24]. These observations concur in indicating a minimal risk for localized endothelial injury and thus of subsequent vasospasm and development of intimal hyperplasia at the site of operative manipulation of the coronary artery [18]. Other techniques such as extravascular balloon occlusion may have the same advantages with regard to short-term consequences on endothelial function. Another issue not addressed by the present study is the patency of coronary anastomosis on a beating heart. Indeed, as long as these anastomoses are not subject to systematic postoperative control, concerns can legitimately be expressed about the risk of compromising the high standards of quality currently achieved by conventional revascularization procedures [25]. Whatever the case may be, it is already reassuring that the techniques currently used for control of the target coronary artery and the ischemia-reperfusion cycle necessary for performance of coronary artery revascularization on the beating heart in minimally invasive CABG do not cause acute alteration of endothelium-dependent relaxation. We advocate the same type of assessment for validating alternative techniques that may be developed for achieving hemostasis during beating heart CABG operations. We thank Lisa Maiofiss for the statistical work and Roselyne Prioux for aid in preparation of the manuscript. Doctor Perrault is supported by the Clinician Scientist program from the Medical Research Council of Canada. References 1. Subramanian VA, Sani G, Benetti FJ, Calafiore AM. Minimally invasive coronary artery bypass surgery: a multicenter report of preliminary clinical experience [Abstract]. Circulation 1995;92(Suppl 1):645. 2. Westaby SW, Benetti FJ. 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Downey RJ, McCormack P, LoCicero J, the Video-Assisted Thoracic Surgery Study Group. Dissemination of malignant tumors after video-assisted thoracic surgery. J Thorac Cardiovasc Surg 1996;111:954 60. 9. Stevens JH, Burdon TA, Peters WS, et al. Port access coronary artery bypass grafting: a proposed surgical method. J Thorac Cardiovasc Surg 1996;111:567 73. 10. Pirk J, Kellovsky P. An alternative to cardioplegia. Ann Thorac Surg 1995;60:464 5.

Ann Thorac Surg PERRAULT ET AL 1997;63:751 5 ENDOTHELIAL FUNCTION AFTER CABG 755 11. Levinson MM, Fooks GS. Coronary grafting using a temporary intraluminal shunt instead of heart-lung bypass. Ann Thorac Surg 1995;60:1800 1. 12. Lick SD, Conti VR, Zwischenberger JB, Kurusz M. Simple technique of left heart bypass. Ann Thorac Surg 1996;61: 1555 6. 13. Buffolo E, Silva de Andrade JC, Branco JNR, Teles CA, Aguiar LF, Gomes WJ. Coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg 1996;61: 63 6. 14. Arom KV, Emery RW, Nicoloff DM. Mini-sternotomy for coronary artery bypass grafting. Ann Thorac Surg 1996;61: 1271 2. 15. Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989;3:2007 18. 16. Vanhoutte PM. The endothelium-modulator of vascular smooth muscle tone. N Engl J Med 1988;319:412 3. 17. Fonger JD, Yang XM, Cohen RA, Haudenschild CC, Shemin RJ. Human mammary artery endothelial sparing with fibrous jaw clamping. Ann Thorac Surg 1995;60:551 5. 18. Gundry S. Discussion of Pfister AJ, Zaki S, Garcia JM, et al. Coronary artery bypass without cardiopulmonary bypass. Ann Thorac Surg 1992;54:1091 2. 19. Shimokawa H, Aarhus L, Vanhoutte PM. Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin. Circ Res 1987;61:256 70. 20. Shimokawa H, Flavahan NA, Vanhoutte PM. Loss of the endothelial pertussis-toxin sensitive G-protein function in atherosclerotic porcine coronary arteries. Circulation 1991; 83:652 60. 21. Pearson PJ, Schaff HV, Vanhoutte PM. Acute impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Circ Res 1990;67:385 93. 22. Pearson PJ, Schaff HV, Vanhoutte PM. Long term impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Circ Res 1990;81:1921 7. 23. Lin PJ, Chang CH, Lee YS, et al. Acute endothelial reperfusion injury after coronary artery bypass grafting. Ann Thorac Surg 1994;58:782 8. 24. Amrani M, Chester AH, Jayakumar J, Yacoub MH. Aging reduces postischemic recovery of coronary endothelial function. J Thorac Cardiovasc Surg 1996;111:238 45. 25. Lytle BW. Minimally invasive cardiac surgery [Editorial]. J Thorac Cardiovasc Surg 1996;111:554 5. Notice From the American Board of Thoracic Surgery The part I (written) examination will be held at the- Atlanta Airport Hilton and Towers, Atlanta Airport, Atlanta, GA, on February 1, 1998. The closing date for registration is August 1, 1997. To be admissible for the part II (oral) examination, a candidate must have successfully completed the part I (written) examination. A candidate applying for admission to the certifying examination must fulfill all the requirements of the board in force at the time the application is received. Please address all communications to the American Board of Thoracic Surgery, One Rotary Center, Suite 803, Evanston, IL 60201. 1997 by The Society of Thoracic Surgeons Ann Thorac Surg 1997;63:755 0003-4975/97/$17.00 Published by Elsevier Science Inc PII S0003-4975(97)00032-9