In the last two decades, the advantage of using arterial

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1 Prevention of Radial Artery Graft Vasospasm After Coronary Bypass Jyotirmay Chanda, MD, Igor Brichkov, BS, and Charles C. Canver, MD Division of Cardiothoracic Surgery, Albany Medical College, Albany, New York Background. Pharmacologic prophylaxis for prevention of notorious radial artery (RA) spasm is critical because of the increasingly routine use of the RA conduit during coronary bypass. Therefore, we investigated the vasodilatory effect of calcium antagonist in combination with nitroglycerin (NTG) RA segments. Methods. We evaluated the vasodilatory effect of nifedipine alone, verapamil alone, diltiazem alone, NTG alone, and calcium antagonist in combination with in endothelin-1 (ET-1)-, angiotensin II (AII)-, 5-hydroxytryptamine (5-HT)-, and norepinephrine (NE)- precontracted human RA rings mounted in organ baths. Results. Nifedipine (10 5 M) alone, diltiazem (10 5 M) alone, verapamil (10 5 M) alone, and NTG (10 5 M) alone showed maximum vasodilatory effect in either 10 7 M ET-1-, 10 7 M AII-, 10 5 M NE-, or 10 4 M 5-HT-precontracted RA segments. The 10 5 M NTG alone-induced vasodilation (88.5% 7.7%) in ET-1- precontracted segments was the highest vasodilation (ANOVA, p ) among NTG alone-induced vasodilatory effects in RA. The relaxing effect of any of the calcium antagonists alone varied from 32.7% 13.2% to 76.5% 20.5% in RA precontracted with different vasoconstrictors. Nearly 200% vasodilation was observed with calcium antagonist in combination with NTG in AII-precontracted vessels. Nonetheless, the vasodilatory effect of calcium antagonist in combination with NTG in RA segments precontracted with different vasoconstrictors other than AII was nearly 100%. Conclusions. A calcium antagonist in combination with NTG is more potent than calcium antagonist alone or NTG alone in prevention of human RA vasospasm after coronary bypass. (Ann Thorac Surg 2000;70:2070 4) 2000 by The Society of Thoracic Surgeons Accepted for publication May 14, Address reprint requests to Dr Canver, Division of Cardiothoracic Surgery, Mail code 55, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208; canverc@mail.amc.edu. In the last two decades, the advantage of using arterial conduits during coronary bypass has been well established. Angiographic demonstration of radial artery (RA) patency in 3 of Carpentier s early patients at 15 to 18 years after grafting has resulted in the reconsideration of using the RA [1]. The rebirth of the RA conduit has seen the most widespread adaptation of a new coronary conduit in the history of arterial conduits [2] and it seems to be better than any other alternative arterial conduits for myocardial revascularization with early and midterm patency rates equivalent to that of pedicled internal thoracic artery [3]. Among various vasoactive substances, endotheliumderived contracting factors such as endothelin, circulating sympathomimetic substances ( adrenoreceptor agonists) such as norepinephrine (NE), platelet-derived contracting substances such as 5-hydroxytryptamine (5-HT), and renin-angiotensin system-related substances such as angiotensin II (AII) play important role in genesis of arterial graft spasm [4]. Although improved drug therapy for coronary graft spasm is now clinically available, vasospasm still occurs in at least 5% to 10% of RA grafts. Diltiazem, which is used empirically to prevent RA vasospasm in patients after coronary artery bypass grafting (CABG), had little effect on human RA contractility [5]. Furthermore oral diltiazem treatment failed to prevent serotonin-induced vasoconstriction on RA grafts used during myocardial revascularization 1 year after the operation [6]. Post-CABG administration of low-dose oral nifedipine kept the RA grafts patent in 96.8% of patients at midterm follow-up period [3]. Similarly, postoperative administration of oral amlodipine for 6 months provided a 91% RA graft patency rate at 1 year [7]. Barner [1] avoided the routine use calcium-channel blockers due to lack of reliable data supporting their clinical benefit, concern over perioperative adverse effects, and primarily the belief that intact functional endothelium in the RA conduit would yield adequate vasodilation. Despite the widespread adoption of increasing use of RA conduit use during CABG, pharmacologic prophylaxis for postoperative RA vasospasm remains unsolved. Therefore the aim of this study was to compare the vasodilatory effects of the calcium antagonists nifedipine, verapamil, and diltiazem alone or in combination with nitroglycerin (NTG) in an in vitro model of a RA vasospasm. Material and Methods Radial Artery Segment Preparation Discarded RA segments were collected from 28 patients undergoing CABG using RA. Permission to use discarded human RA segments was approved by the Insti by The Society of Thoracic Surgeons /00/$20.00 Published by Elsevier Science Inc PII S (00)

2 Ann Thorac Surg CHANDA ET AL 2000;70: RADIAL ARTERY VASOSPASM 2071 American Regent) in vascular rings precontracted with the concentration (maximum concentration) of vasoconstrictors that caused maximum vasoconstriction. Vasodilator was added to the bath after complete vasoconstriction with a particular vasoconstrictor. Once the maximum vasodilation was achieved with a given vasodilator, the vascular ring was washed with PSS four to five times every 10 to 15 minutes. Usually the interval between the vasodilation and next vasoconstriction was 45 minutes to 1 hour. Fig 1. Concentration-contraction curves of radial artery to endothelin (ET-1), angiotensin II (AII), 5-hydroxytryptamine (5-HT), and norepinephrine (NE). tutional Review Board of Albany Medical College. Discarded vessels were immediately collected and placed into a container with cold physiologic salt solution (PSS) consisting of 140 mmol/l NaCl, 4.7 mmol/l KCl, 1.2 mmol/l NaH 2 PO 4, 2.0 mmol/l 3-[N-Morpholino]propanesulfonic acid (MOPS), 0.02 mmol/l disodium ethylenediaminetetraacetic acid (Na 2 EDTA), 1.6 mmol/l CaCl 2, 1.2 mmol/l MgSO 4, 1 g/l dextrose, ph 7.4. The vessels were placed in a dish containing PSS, dissected out from their surrounding connective tissue, and cut into rings 3 to 4 mm long. The number of rings provided by each patient varied from four to eight. Vessel rings were mounted on wire hooks (Radnoti Tissue Support, Radnoti Glass Technology Inc, Monrovia, CA) with one end connected to an isometric force-displacement transducer FT03 (Grass Instrument Company, Quincy, MA) and then suspended in PSS in water-jacketed organ baths (Radnoti). The force-displacement transducer was linked to a bridge amplifier (Gould Instruments S.A.F., Ballainvilliers, France) and a thermal recorder (Gould) to give continuous record of tension in vessel segment. The solution in organ baths was aerated with a gas mixture of 95% O 2 and 5% CO 2 and maintained at 37 C. Every effort was made not to damage the endothelium while dissecting and mounting the vascular rings. Radial artery segments were progressively stretched to a resting force of 3.5 to 4.0 grams and allowed to equilibrate for 90 to 120 minutes. Concentration contraction curves were constructed as follows: vascular rings from same patient s arterial segment were separately exposed to 0.5 log unit increments of endothelin-1 (ET-1; American Peptide Co, Sunnyvale, CA), AII (Sigma, St. Louis, MO), 5-HT (Sigma), and NE (Abbott Laboratories, North Chicago, IL) added to the organ bath (Fig 1). Concentrations that induced maximal contraction were subsequently used to generate a vasospasm. Vasodilation was induced with nifedipine ( 10 to 4 logm, Sigma), verapamil ( 10 to 4 logm, American Regent Lab Inc, Shirley, NY), or diltiazem ( 10 to 4 logm, Abbott) alone, or in combination with NTG ( 10 to 4 logm Statistical Analysis The data were reported as mean standard deviations of the mean. Values were compared by means of repeatedmeasures analysis of variance (ANOVA) complex compact variable techniques (StatView version 5.0.1, SAS Institute Inc, San Francisco, CA). Multiple comparisons were carried out with Fisher s protected least significant difference test. A p value less than 0.05 was considered statistically significant. Results Endothelin-1 (10 7 M) (effective drug concentration producing 50% of maximum contraction calculated from contraction response curves of every segment, EC logm), 10 7 M AII (EC logm), 10 4 M 5-HT (EC logm), and 10 5 MNE (EC logm) evoked maximum contraction (ET-1, grams; AII, grams; 5-HT, grams; NE, grams; one-way ANOVA, p 0.234) of RA segments (Fig 1). The use of 10 5 M nifedipine alone, 10 5 M diltiazem alone, 10 5 M verapamil alone, and 10 5 M NTG alone showed maximum vasodilatory effect in 10 7 M ET-1-, 10 7 M AII-, 10 5 M NE-, and 10 4 M 5-HT-precontracted RA segments. As 10 5 M NTG alone was the highest concentration to produce maximum vasorelaxation of RA, in combined preparation we have arbitrarily chosen to add 10 6 M NTG with 10 5 M calcium antagonist. The vasodilatory effect of calcium antagonist alone, NTG alone, and calcium antagonist in combination with NTG in ET-1-, AII-, 5-HT-, and NE-precontracted RA segments are shown in Figure 2. Radial Artery Vasodilation Induced With Nitroglycerin Alone The 10 5 M NTG alone-induced vasodilation (88.5% 7.7%) in ET-1-precontracted segments was the highest vasodilation (p ) among NTG alone-induced vasodilatory effects in RA segments precontracted with different vasoconstrictors. Even this value was significantly higher (p 0.038) than that of 10 6 M NTG alone-induced vasodilation (75.4% 21%) in ET-1- precontracted segments. However, 10 5 M NTG aloneinduced vasodilation in NE-, 5-HT-, and AIIprecontracted RA segments did not differ significantly from that of 10 6 M NTG alone-induced vasodilation in NE-, 5-HT-, and AII-precontracted RA (Fig 2).

3 2072 CHANDA ET AL Ann Thorac Surg RADIAL ARTERY VASOSPASM 2000;70: Fig 2. Vasodilatory effect of 10 5 M nifedipine (Nif) alone, 10 5 M diltiazem (Dil) alone, 10 5 M verapamil (Vp) alone, 10 5 M NTG (NTG5) alone, 10 6 M NTG (NTG6) alone, and 10 6 M NTG in combination with 10 5 M diltiazem (Dil NTG), 10 5 M nifedipine (Nif NTG), and 10 5 M verapamil (Vp NTG) in endothelin-1 (ET-1)-, angiotensin II (AII)-, 5-hydroxytryptamine (5-HT)-, and norepinephrine (NE)-precontracted radial artery segments. Radial Artery Vasodilation Induced With Calcium Antagonist Alone The vasodilatory effect of NTG alone or calcium antagonist alone in AII-precontracted arteries, was similar to their counterparts in ET-1-, NE-, or 5-HT-precontracted segments. The relaxing effect of either nifedipine alone, diltiazem alone, or verapamil alone varied in RA precontracted with different vasoconstrictors. Nifedipineinduced vasodilation (68.7% 18%) in ET-1- precontracted segments was significantly (p 0.002) higher than that (32.7% 13.2%) in 5-HT-precontracted vessels. However, verapamil-induced vasodilation (76.5% 20.5%) in NE-precontracted arteries was the highest vasodilatory effect among calcium antagonists only in RA precontracted with the other vasoconstrictors (Fig 2). Radial Artery Vasodilation Induced With Calcium Antagonist in Combination With Nitroglycerin Nearly 200% vasodilation was noticed with calcium antagonist in combination with NTG in AII-precontracted vessels. The vasodilatory effect of calcium antagonist in combination with NTG in AII-precontracted vessels (verapamil NTG, 219% 31.7%; diltiazem NTG, 224.3% 51.6%; nifedipine NTG, 205.4% 23.9%; p NS) was significantly (ANOVA, p ) higher than that of calcium antagonist in combination with NTG in vessels contracted with any other vasoconstrictors (Table 1, Fig 2). Comment The findings in this study demonstrate that the vasodilating effect of calcium antagonist in combination with NTG is superior to either the calcium antagonist alone or NTG alone in RA undergoing a vasospasm in vitro. Similar to other arterial conduits, the RA is susceptible to spasm during harvesting. Because the media of the RA is significantly thicker than the media of other arterial conduits [8], the spasm is more intense and more difficult to reverse. Chardigny and colleagues [9] showed that the RA has greater contractile response to NE and serotonin compared with the internal thoracic artery. 5-Hydroxytryptamine contracts vascular smooth muscle directly through 5-HT 2 receptors [10]. When endothelium is lost, perhaps also when it is damaged, platelets aggregate in the area where endothelium is denuded and release substances such as 5-HT that strongly contract smooth muscle. 5-Hydroxytryptamine has been suggested to be an important spasmogen in coronary artery spasm even when endothelium is present [11]. Experiments showing potent vasoconstrictor effects of media obtained from cultured aortic endothelial cells suggested the existence of an endothelium-derived vasoconstrictor ET-1 [12]. The endothelin-a receptor is selective for ET-1 and causes vasoconstriction. A variety of pathophysiologic disorders are associated with increased circulating plasma levels of endothelin. It was demonstrated that the concentration of endothelin in the coronary sinus is increased during CABG [13]. He and Yang [14] demonstrated that RA has higher contractile response to ET-1 and contracts more strongly to ET-1 and AII. In our experiment among several vasoconstrictors (ET-1, AII, NE, and 5-HT), although not statistically significant (p 0.234), ET-1 caused the maximum vasoconstrictor effect in RA segments (Fig 1). Roubos and associates [15] reported that pharmacologic treatment of the saphenous vein with a solution containing glyceryl trinitrate and verapamil during harvesting allows the use of a lower distension pressure, reduces the breakdown of high-energy phosphates, and Table 1. Vasodilatory Effect of NTG in Combination With Nif, Dil, and Vp in 5-HT-, ET-1-, NE-, and AII- Precontracted Radial Artery Segments Vasoconstrictor Vasodilator Relaxation (%) Dil NTG HT Nif NTG Vp NTG Dil NTG ET-1 Nif NTG Vp NTG Dil NTG NE Nif NTG Vp NTG Dil NTG All Nif NTG Vp NTG Concentrations: 10 6 M NTG; 10 5 M Dil; 10 5 M Nif; 10 5 M Vp. AII angiotensin II; Dil diltiazem; ET-1 endothelin-1; 5-HT 5-hydroxytryptamine; NE norepinephrine; Nif nifedipine; NTG nitroglycerin; Vp verapamil.

4 Ann Thorac Surg CHANDA ET AL 2000;70: RADIAL ARTERY VASOSPASM 2073 improves endothelial coverage in the vein wall. He and Yang [16, 17] studied the effects of verapamil in combination with NTG on prevention of the contraction of the RA during operation, and in another study [14], demonstrated the necessity of the use of vasodilator solutions for RA as this artery is particularly sensitive to receptor agonists such as ET-1 and AII. In fact, with the introduction of calcium antagonists, vasospasm of the RA is less frequently encountered and the early results have been significantly improved [2], although the long-term results still remain to be determined. He and Yang achieved 100% vasodilation with M verapamil in combination with M NTG in 25 mmol/l KClprecontracted RA [16]. Except for these studies [16, 17], the vasodilatory effect of calcium antagonists in combination with NTG in RA segments precontracted with different vasoconstrictors has not been reported thus far. Shapira and colleagues [18] found that NTG is a superior coronary bypass conduit vasodilator and is more effective in preventing graft spasm than diltiazem. Gurevitch and colleagues [19] used high-dose isosorbide dinitrate in patients undergoing myocardial revascularization with composite arterial grafts. At a mean follow-up of 24 months, all hospital survivors were alive, with 97% being angina free; 97% of the angiographically studied anastomoses were patent [20]. Unfortunately, a major potential limitation of the use of nitrates is the development of tolerance. It is assumed that NTG tolerance results in part from these neurohormonal adjustments and intravascular volume expansion [20]. Although Gurevitch and coworkers [19] and He and Yang [14, 21] demonstrated nearly 100% relaxation with NTG alone in thromboxane A 2 mimetic U46619-precontracted RA, we have never achieved that much vasodilation with NTG alone in RA segments precontracted with ET-1, AII, or 5-HT. In our study NTG-induced vasodilation varied in RA segments precontracted with different vasoconstrictors; 10 5 M NTG alone-induced vasodilation in ET-1-precontracted segments was the highest vasodilation (p ) among NTG alone-induced vasodilatory effects in differently precontracted RA segments. This value was significantly higher than even that of 10 6 M NTG alone in ET-1-precontracted segments. Surprisingly, vasodilation induced with 10 5 M NTG alone in NE-, 5-HT-, or AII-precontracted RA segments was significantly less than that with even 10 6 M NTG alone in ET-1-precontracted segments. Diltiazem, a calcium-channel blocker, has been selected empirically by most surgeons to minimize the post-cabg RA vasospasm [22, 23]. However, diltiazem does not appear to be capable of eliminating postoperative RA spasm. Yang and He [24] reported nearly 100% relaxation of 25 mmol/l KCl-precontracted RA with calcium antagonist alone. Cable and colleagues [5] reported that verapamil had little effect on radial receptordependent and receptor-independent contraction, whereas nifedipine and NTG were much more effective. However, we have observed that the relaxing effect of nifedipine alone, diltiazem alone, or verapamil alone varied in RA precontracted with different vasoconstrictors. Nifedipine alone-induced vasodilation in ET-1- precontracted segments was significantly higher than that in 5-HT-precontracted vessels. Although the exact mechanism is unknown, verapamil-induced vasodilation in NE-precontracted arteries in our study was the highest vasodilatory effect among calcium antagonists only in RA precontracted with different vasoconstrictors. In terms of the vasodilatory effect on RA segments, these data do not support the notion that any one calcium antagonist is superior. Instead, the efficacy of each calcium antagonist varies with the mediator of vasoconstriction that it is acting against. The reason why the effect of nearly 200% vasodilation with calcium antagonist in combination with NTG was observed only in AII-precontracted vessels remains unknown. Nonetheless, the effect of nearly 100% vasodilation observed in RA segments precontracted with agents other than AII was enough to satisfy our goal. In summary, calcium antagonist in combination with NTG is the most potent available pharmacologic regimen capable of preventing RA vasospasm in a patient undergoing CABG using the RA conduit. The authors are grateful for the help of John M. Kelley, MD, Linda Altieri, RN, and Arnold Villajuan, RN. References 1. Barner HB. The continuing evolution of arterial conduits. Ann Thorac Surg 1999;68:S Acar C, Jebara V, Pagny JY, et al. Five-year results of coronary artery bypass grafting using the radial artery. J Thorac Cardiovasc Surg 1998;116: Bhan A, Gupta V, Choudhary SK, et al. Radial artery in CABG: could the early results be comparable to internal mammary artery graft? Ann Thorac Surg 1999;67: He G-W. Arterial grafts for coronary artery bypass grafting: biological characteristics, functional classification, and clinical choice. Ann Thorac Surg 1999;67: Cable DG, Caccitolo JA, Pearson PJ, et al. New approaches to prevention and treatment of radial artery graft vasospasm. Circulation 1998;98:II Sperti G, Manasse E, Kol A, et al. Comparison of response to serotonin of radial artery grafts and internal mammary grafts to native coronary arteries and the effect of diltiazem. Am J Cardiol 1999;83: Tatoulis J, Buxton BF, Fuller JA. Bilateral radial artery grafts in coronary reconstruction: technique and early results in 261 patients. Ann Thorac Surg 1998;66: Van Son JA, Smedts F, Vincent JG, Van Lier HJ, Kubat K. Comparative anatomic studies of various arterial conduits for myocardial revascularization. J Thorac Cardiovasc Surg 1990;99: Chardigny C, Jebara VA, Acar C, et al. Vasoreactivity of the radial artery. Comparison with the internal mammary artery and gastroepipoic arteries with implications for coronary artery surgery. Circulation 1993;88:II Cocks TM, Angus JA. Endothelium-dependent relaxation of coronary arteries by norepinephrine and serotonin. Nature 1983;305: Fukai T, Egashira K, Hata H, et al. Serotonin-induced coronary spasm in a swine model. A minor role of defective endothelium-derived relaxing factor. Circulation 1993;88: Hickey KA, Rubanyi G, Paul RJ, Highsmith RF. Character-

5 2074 CHANDA ET AL Ann Thorac Surg RADIAL ARTERY VASOSPASM 2000;70: ization of a coronary vasoconstrictor produced by cultured endothelial cells. Am J Physiol 1985;248:C Franco-Cereceda A, Barr G, Owall A, Liska J, Lundberg JM. Is endothelin-1 release at reperfusion of the ischaemic human heart due to cold-induced displacement of endothelin from binding sites? Eur J Pharmacol 1995;279: He G-W, Yang C-Q. Radial artery has higher receptormediated contractility but similar endothelium function compared to mammary artery. Ann Thorac Surg 1997;63: Roubos N, Rosenfeldt FL, Richards SM, Conyers RA, Davis BB. Improved preservation of saphenous vein grafts by the use of glyceryl trinitrate-verapamil solution during harvesting. Circulation 1995;92:II He G-W, Yang C-Q. Use of verapamil and NTG solution in preparation of radial artery for coronary grafting. Ann Thorac Surg 1996;61: He G-W. Verapamil plus NTG solution maximally preserves endothelial function of the radial artery: comparison with papaverine solution. J Thorac Cardiovasc Surg 1998;115: Shapira OM, Xu A, Vita JA, et al. Nitroglycerin is superior to diltiazem as a coronary bypass conduit vasodilator. J Thorac Cardiovasc Surg 1999;117: Gurevitch J, Miller HI, Shapira I, et al. High-dose isosorbide dinitrate for myocardial revascularization with composite arterial grafts. Ann Thorac Surg 1997;63: Munzel T, Heitzer T, Kurz S, et al. Dissociation of coronary vascular tolerance and neurohormonal adjustments during long-term NTG therapy in patients with stable coronary artery disease. J Am Coll Cardiol 1996;27: He G-W, Yang C-Q. Comparison of the vasorelaxant effect of nitroprusside and NTG in the human radial artery in vitro. Br J Clin Pharmacol 1999;48: Sudhakar CB, Forman DL, Dewar ML, Shaw RK, Fusi S. Free radial artery grafts: surgical technique and results. Ann Plast Surg 1998;40: Weinschelbaum EE, Gabe ED, Macchia A, Smimmo R, Suarez LD. Total myocardial revascularization with arterial conduits: radial artery combined with internal thoracic arteries. J Thorac Cardiovasc Surg 1997;114: Yang C-Q, He G-W. Comparison of effect of calcium antagonist in the human radial artery. FASEB J 1999;13:A93. Discussion Groups on the Internet The following three articles will be published in the January 2001 issue of The Annals of Thoracic Surgery, and have been selected for discussion topics on the Internet. These discussion groups can be accessed by going to the Society of Thoracic Surgeons Home Page ( and clicking on Discussion Forums. We encourage everyone to participate, as our goal is to make the discussion as interactive as possible. The Radial Artery Versus the Saphenous Vein Graft in Contemporary CABG: A Case-Matched Study Gideon Cohen, MD, Miguel G. Tamariz, MD, Jeri Y. Sever, Negin Liaghati, BSc, Veena Guru, MD, George T. Christakis, MD, Gopal Bhatnagar, MD, Charles Cutrara, MD, Labib Abouzahr, MD, Bernard S. Goldman, MD, and Stephen E. Fremes, MD When to Discontinue Extracorporeal Membrane Oxygenation for Postcardiotomy Support Steven M. Fiser, MD, Curtis G. Tribble, MD, Aditya K. Kaza, MD, Stewart M. Long, MD, Richard K. Zacour, CCP, John A. Kern, MD, and Irving L. Kron, MD Valvuloplasty With Glutaraldehyde-Treated Autologous Pericardium in Patients With Complex Mitral Valve Pathology Choi-Keung Ng, MD, Joachim Nesser, MD, Christian Punzengruber, MD, Otmar Pachinger, MD, Johannes Auer, MD, Herbert Franke, MD, and Peter Hartl, MD Tom R. Karl, MD Internet Annals Editor Philadelphia, Pennsylvania karl@ .chop.edu by the Society of Thoracic Surgeons Ann Thorac Surg 2000;70: /00/$20.00 Published by Elsevier Science Inc PII S (00)