In the early 1970s, Carpentier and colleagues [1] proposed

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1 Pathology of the Radial and Internal Thoracic Arteries Used as Coronary Artery Bypass Grafts Eric Kaufer, BS, Stephen M. Factor, MD, Rosemary Frame, MS, and Richard F. Brodman, MD Departments of Cardiothoracic Surgery and Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York Background. This investigation compared the incidence and the degree of atherosclerosis present in radial artery (RA) and internal thoracic artery segments remaining after coronary artery bypass grafting. Methods. One hundred seventy specimens from 102 patients were histologically analyzed, including 106 RA specimens. Results. The mean degree of pathology for the RA was 0.89 on a 0 (none) to 4 (lumen completely obliterated) scale; the mean grade of pathology for the internal thoracic artery was 0.30 (p < 0.001). Presence of diabetes, aortofemoral disease, femoral-popliteal disease, age, and male gender correlated with an increase in RA pathology. Flow in the in situ RA did not correlate with the degree of pathology. Conclusions. Study of the excess RA and internal thoracic artery segments remaining after coronary artery bypass grafting demonstrated that the RA had a higher degree of atherosclerosis than the internal thoracic artery at the time of harvest. Overall severity of disease in the RA was low. The long-term performance of RA grafts will determine whether this level of atherosclerotic disease has any clinical significance. (Ann Thorac Surg 1997;63: ) 1997 by The Society of Thoracic Surgeons In the early 1970s, Carpentier and colleagues [1] proposed the use of the radial artery (RA) as a coronary artery bypass graft; its use was abandoned soon thereafter because 32% of the RA grafts were found to be occluded, with an additional 32% demonstrating severe generalized stenosis [2, 3]. There has been a recent resurgence in the use of the RA as a viable conduit after the discovery that three RA grafts from the Carpentier series, which were thought to be occluded in the early postoperative period, were found to be patent and free of visible atherosclerotic lesions on angiography approximately 15 years after operation [3]. Early RA patency rates ( 1 year) in the current surgical era, including our own series, are more than 90% [3 5]. The current, high early patency rates have been attributed to refinement of the harvesting and preparation techniques coupled with the use of calcium-channel blockers not available in the 1970s [3, 6]. Given the recent increase in interest for use of the RA as a coronary artery bypass graft conduit [7], this investigation evaluated the incidence and the degree of atherosclerosis present in segments of the RA left after use as coronary artery bypass grafts and compared these findings with the incidence and degree of atherosclerosis of excess internal thoracic artery (ITA) segments. Material and Methods Institutional review board approval for RA harvest was granted in June All patients signed informed consent for the use of the RA as a bypass conduit. One Accepted for publication Nov 6, Address reprint requests to Dr Brodman, Department of Cardiothoracic Surgery, Montefiore Medical Center, 111 E 210 St, Bronx, NY hundred six RA segments remained after coronary artery bypass grafting from 102 of the first 150 patients undergoing coronary artery bypass grafting using RA grafts. Any portion of either the RA or ITA that was harvested but not used as a bypass graft was histologically evaluated. Comorbidities that may influence atherogenesis were recorded prospectively. Specimens were prospectively collected, representing either the proximal or the distal region of the RA graft, rather than the center, which was used as the bypass conduit. Six to 24 sections were analyzed per segment of artery submitted for histologic evaluation; specimens were fixed with 5% formaldehyde, cross-sectioned at 4 m, and mounted. Specimens were stained with hematoxylin and eosin. Retrospectively, a blinded, independent reader graded each specimen for degree of atherosclerosis based on the ratio of the thickness of the intima and the media of the artery at the point of maximal intimal thickening. The specimens were graded as follows (adapted from Kobayashi and colleagues [8]): grade 0, intima-to-media ratio less than or equal to 0.25; grade 1, intima-to-media ratio greater than 0.25 but less than or equal to 0.5; grade 2, intima-to-media ratio greater than 0.5 but less than or equal to 0.75; grade 3, intima-to-media ratio greater than The grade was increased by one if the lesion was diffuse, indicating that the intimal thickening included more than 50% of the cross-sectional circumference. A grade of 4 was also given when the lumen had been completely obliterated by thickening or thrombosis, or both. For each specimen, the grade was derived from that section with the most advanced observed disease by The Society of Thoracic Surgeons /97/$17.00 Published by Elsevier Science Inc PII S (96)

2 Ann Thorac Surg KAUFER ET AL 1997;63: RADIAL AND INTERNAL THORACIC ARTERY PATHOLOGY 1119 Among the preoperative tests performed is a perfusion index, which is used to determine whether collateral flow in the forearm and hand will allow safe harvest of the RA. Perfusion index is a measure of change in the length of the path of light through the finger, from the nail bed to the skin on the fingertip pulp, using a modified Ohmeda Biox 3700 pulse oximeter (Ohmeda Inc, Louisville, CO). The perfusion index has been correlated with digital blood flow [9]; the perfusion index obtained with the probe on the thumb during ulnar artery occlusion is a measure of the flow of blood through the RA. The blood flow through the RA was correlated to the degree of RA pathology. Data Analysis Data were analyzed using SPSS for Windows, Version 6.1 (SPSS, Inc, Chicago, IL). Significance was set at a p value of 0.05 or less. A correlation matrix was generated to evaluate the association between risk factors and degree of pathology in the RA and ITA specimens; a second correlation matrix was generated to evaluate the association of blood flow as measured by the perfusion index ratio to the degree of pathology in the RA. Variables with significant correlations were analyzed by multivariate regression. A paired t test was performed to compare the degree of pathology between the ITA and RA specimens from the same patient. Results There was a total of 170 specimens from 102 patients. There were 106 RA specimens, 2 right ITA specimens and 62 left ITA specimens. After being graded for degree of atherosclerosis, given the small number of right ITA specimens, these specimens were combined with the left ITA specimens for all analyses. There were 77 men and 25 women; age was years (mean SD), body surface area was m 2, and left ventricular ejection fraction was The incidence of the atherosclerotic risk factors within our population is as follows: Prior smoking history 65.0% Cholesterol level 250 mg/dl 61.5% Hypertension 59.8% Positive family history 41.8% Diabetes 37% Type I 44.7% Type II 55.3% Femoral-popliteal atherosclerosis 19.8% Aorto-femoral atherosclerosis 8.1% Chronic renal failure (creatinine 2.5 mg/dl) 1.0% The degree of atherosclerosis for both the ITA and RA specimens is summarized in Table 1. The mean grade for the 64 ITA specimens is , and for the 106 RA specimens, it is When comparing the RA specimen with the corresponding ITA specimen from the same patient, the mean ITA grade is , and the Table 1. The 170 Specimens Graded by Degree of Atherosclerosis Grade RA (n 106) RITA (n 2) LITA (n 62) 0 49 (46.2%) 2 (100%) 48 (77.4%) 1 27 (25.5%) 10 (16.1%) 2 21 (19.8%) 4 (6.5%) 3 7 (6.6%) (1.9%) 0 Mean grades LITA left internal thoracic artery; RA radial artery; RITA right internal thoracic artery. mean RA grade is (p 0.001). There were only 5 patients with both proximal and distal RA segments available for analysis. There is no difference in the graded degree of atherosclerosis for each pair. Three pairs were graded 0, one pair as grade 1, and one pair as grade 3. Figure 1 demonstrates examples for each grade of RA pathology. Analysis of the correlation matrix demonstrated a weak but statistically significant positive correlation between the degree of atherosclerosis in the RA and the presence of diabetes (r ; p 0.038) and the presence of aortoiliac atherosclerosis (r ; p 0.025). There was a moderate, statistically significant correlation between RA atherosclerosis and sex (r ; p 0.001), with men more prone to higher degrees of atherosclerosis than women; age (r ; p 0.001), with increased atherosclerosis noted with increased age; and the presence of femoral-popliteal atherosclerosis (r ; p 0.001). Body surface area (r ; p 0.762), left ventricular ejection fraction (r ; p 0.810), smoking (r ; p 0.560), high cholesterol levels (r ; p 0.970), and family history of coronary disease (r ; p 0.170) did not correlate with the degree of atherosclerosis in the RA specimens. Multivariate regression demonstrated that sex, age, presence of diabetes, aortoiliac atherosclerosis, and femoral-popliteal atherosclerosis explained a total of 60.67% of the variance (p 0.001). There was no significant correlation between the above risk factors and the degree of ITA pathology. The mean perfusion index obtained during ulnar artery occlusion for all patients was ; for patients with RA specimens graded 0 to 1, it was , and for grade 2 or more, it was (p 0.342). There was an extremely weak, negative correlation between the amount of flow as determined by the perfusion index and the degree of pathology (r , p 0.476). For specimens with a grade more than 2, a weak, negative correlation was also noted (r , p 0.245). Two patients in this series had RAs harvested that were not used as conduits. The first graft was not used because of an extremely small luminal diameter (1 mm); her pathology specimen was grade 0. The second patient did not have her harvested RA used because of extensive atherosclerosis and grossly small luminal diameter. Two

3 1120 KAUFER ET AL Ann Thorac Surg RADIAL AND INTERNAL THORACIC ARTERY PATHOLOGY 1997;63: Fig 1. Photomicrographs of radial artery sections illustrating the various grades of atherosclerosis ( 60 before 50% reduction): (A) grade 0; (B) grade 1; (C) grade 2; (D) grade 3; (E) grade 4. There is some variation in cross-sectional size related to cutting artifact and actual variation of the vessel caliber from patient to patient. additional patients had severe localized atherosclerosis; the stenotic portion was trimmed in both patients, and the remainder of the grafts used for bypass grafting. In the 3 patients with atherosclerosis, preoperative evaluations suggested the probability of atherosclerosis in the RA as low to absent flow through the RA was noted during the preoperative evaluation of collateral flow to the hand. Two of the specimens were grade 4 (the only 2 specimens graded as such), and the third was grade 3. Diffuse peripheral vascular disease was present in 2 of these patients: 1 had bilateral femoral bruits and no palpable pulses below the femoral arteries, and the second had mesenteric, splenic, and renal artery stenosis. Comment Although 72% of the RA specimens were grade 0 or 1, 28% of the RA specimens had more than 50% atheroscle-

4 Ann Thorac Surg KAUFER ET AL 1997;63: RADIAL AND INTERNAL THORACIC ARTERY PATHOLOGY 1121 rotic changes in the intima. Unlike the ITA, the RA may be subject to intraluminal trauma from previous RA cannulation for arterial blood pressure monitoring or blood gas sampling. On the basis of the low correlation between the degree of RA pathology and known coronary artery disease risk factors, such as smoking, hypercholesteremia, and obesity, it appears that some coronary artery risk factors do not appreciably affect the development of atherosclerosis in the RA. Others, such as diabetes, do appear to affect the development of atherosclerosis in the RA. The ITA is known to be relatively resistant to the development of atherosclerosis in the presence of risk factors for vascular disease [10]; our findings are consistent with these observations. There is an obvious need for a bypass conduit to be relatively free of disease before implantation. To evaluate the propensity of the in situ RA to have development of atherosclerosis, we compared the thickness of the intima at its widest point with that of the media at the same location. This method was similar to the methodology used by Kobayashi and colleagues [8] in their study of ITA pathohistology and is likely more sensitive to the presence of early atherosclerotic changes than percentage of luminal occlusion, a measurement that has been used in other related studies [11]. Arteries in which intimal hyperplasia develops have been shown to enlarge their caliber to preserve luminal area [12]; therefore, these early atherosclerotic changes can take place without compromising luminal cross-sectional area. The large diameter of the RA may also contribute to preservation of flow. These observations may help to explain the low correlation between the degree of atherosclerosis in the RA compared with flow as measured by the perfusion index, including the specimens with higher grade pathology. Given that the flow is unimpaired, the value of the RA as a bypass conduit is still maintained. Another feature of atherosclerosis is its segmental quality. Therefore, the extent of disease in one section of a vessel does not necessarily define the condition of the entire vessel. The only solution to this problem is to section serially the entire length of the artery. However, this was not possible, as the majority of each RA harvested was used during the operation. The length of the RAs harvested was cm; the length of the RA used was cm. Therefore, about 15% of the RA harvested was available for histologic examination. A similar length of ITA was also studied histologically, although only the distal segment was available as all left ITA grafts in this series were pedicled. We have dealt with this limitation of this study in two ways. The first was to study a relatively large number of specimens. The second was the grading of multiple histologic sections for each specimen. The grade for each specimen was derived from the most severely diseased portion evaluated, making it less likely to underestimate the extent of disease in the remainder of the vessel not evaluated. Furthermore, angiograms were performed approximately 12 weeks postoperatively in 60 patients. There were 92 RA and 62 ITA distal anastomosis. The angiographic findings were previously reported [5]; segmental luminal narrowing of the RA free grafts and the pedicled left ITA grafts was rarely seen. There have been perceived but not real drawbacks to using the RA [7]. The internal elastic lamina of the RA has fenestrations that allegedly predispose to the development of atherosclerosis, but these are also seen in the internal elastic lamina of most arteries, including the ITA [13, 14]. Because of its muscular character, the RA is prone to spasm, which is not unique to the RA [15 17]. However, spasm in arteries may be controlled using calcium-channel blockers, such as diltiazem (Marion Merrell Dow Inc, Kansas City, MO) [3, 18]. Consistent with the study by He and associates [19] of the inferior epigastric artery where a higher degree of atherosclerosis was found in the inferior epigastric artery specimens than in the ITA, our histologic evaluation of the RA and ITA also demonstrated that the RA had a higher degree of atherosclerosis than the ITA at the time of harvest. However, the severity of disease in the RA was low, with a mean grade of only The high early patency rates that have been reported by a number of researchers [3 5, 20, 21] confirm the relative lack of clinical significance of RA atherosclerosis in those arteries harvested for use. The long-term performance of RA grafts will determine whether this level of atherosclerotic disease translates to adverse clinical outcomes. The RA is capable of long-term patency as noted by Acar and colleagues [3] in 3 patients at approximately 15 years of follow-up. Coltharp [22] cited a 51% occlusion rate in 61 RA grafts studied 7 days to 16.3 years after operation. On the basis of the results of this series from the earlier time frame of clinical use of RA for coronary artery bypass graft, it was estimated that the 5-year patency rate for RA grafts would be 65%, and at 10 years, the patency rate, 60%. More recently, at approximately 5 years after operation, Acar (personal communication, February 1996) reports an 83.3% patency rate (10 of 12 patients recatheterized). These results support the finding that early occlusion is attributable to intimal hyperplasia, as those grafts that are patent at 5 years are likely to remain patent. Intimal hyperplasia may be avoided by harvesting the RA together with its vena comitantes and avoidance of mechanical luminal dilation, both probably causally related to the higher occlusion rates seen in the 1970s. In conclusion, the radial artery has many anatomic, surgical, and histologic advantages over other alternative arterial conduits. This study has shown that the RA may be relatively resistant to atherosclerotic development in patients with coronary artery disease, although somewhat less so than the ITA. References 1. Carpentier A, Guermonprez JL, Deloche A, Frechette C, DuBost C. The aorta-to-coronary radial artery bypass graft: a technique avoiding pathological changes in grafts. Ann Thorac Surg 1973;16: Curtis JJ, Stoney WS, Alford WC Jr, Burrus GR, Thomas CS Jr. Intimal hyperplasia: a cause of radial artery aortocoronary bypass graft failure. Ann Thorac Surg 1975;20:

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